Quinazoline derivatives

ABSTRACT

A compound of the formula (I) 
                         
or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof has a superior tyrosine-specific protein kinase inhibitory activity and is useful as a pharmaceutical agent, particularly as an agent for the prophylaxis or treatment of various cancers, psoriasis or diseases caused by arteriosclerosis, and the like.

This application is a U.S. national stage of International ApplicationNo. PCT/JP02/01575 filed Feb. 21, 2002.

TECHNICAL FIELD

The present invention relates to a novel quinazoline derivative. Moreparticularly, the present invention relates to a quinazoline derivativehaving a tyrosine-specific protein kinase (hereinafter tyrosine kinase)inhibitory activity.

The present invention also relates to a pharmaceutical compositioncontaining said quinazoline derivative and a pharmaceutically acceptablecarrier, a tyrosine kinase inhibitor containing said quinazolinederivative, and an anticancer agent and an agent for the treatmentand/or prophylaxis of the diseases based on arteriosclerosis and thediseases caused by the potentiation of tyrosine kinase activity, such aspsoriasis and the like.

BACKGROUND ART

In chemotherapy of cancer, a number of pharmaceutical agents thatinhibit DNA synthesis or that directly inhibit cell division have beenused. These pharmaceutical agents function as cytotoxicity, andsometimes prove effective against rapidly dividing cancer cells. In manycases, however, since the cytotoxicity is not limited to cancer cells,they exhibit strong toxicity in normal cells as well. As the currentsituation stands, therefore, side effects have become a problem inchemotherapy using such pharmaceutical agents. As a different approachacting on a mechanism other than the one mentioned above, a methodenhancing the selectivity to suppress growth of cancer cells is known.

Tyrosine kinase is an enzyme that phosphorylates tyrosine residue inproteins. It is widely known that tyrosine kinase plays an important andcentral role in differentiation and proliferation of cells and in anintracellular signal transduction system. Furthermore, it is alsoconsidered that a failure to control tyrosine kinase activity causesaberration in differentiation or proliferation of cells and in anintracellular signal transduction system, thereby directly causing theonset of many diseases. For example, tyrosine kinase activity has beenfound to be detected more often in arteriosclerosis [Am. J. Physiol.,1991, 260 (4-part 1), C721-C730; Biochem. Biophys. Res. Commun., 1993,192(3), 1319-1326. etc.] and psoriasis [J. Invest. Deruatol., 1990, 95,75-95], as well as in tumor cells than in normal cells [Cell, 1987, 50,823]. Particularly, it has been clarified that growth factor receptortyrosine kinases (hereinafter to be referred to as receptor tyrosinekinase) such as HER2 (also called ErbB2 or Neu), EGF receptor and thelike are deeply involved in the formation of malignant tumor, and thatreceptor tyrosine kinase activity is potentiated in human cancer [CancerRes., 1991, 51, 4430-4435; Cancer Res., 1992, 52, 3636-3641; CancerChemother. Pharmacol., 1993, 32, 1-19 and the like]. Moreover, thesereceptor tyrosine kinases have been shown to excessively express in manytumors such as those in brain, lung, stomach, colorectum, pancreas, headand neck portion, esophagus, bladder, kidney, prostate, ovary, breast,uterus, thyroid gland and the like [Med. Bull., 1991, 47, 87; Expert.Opin. Invest. Drugs, 1994, 3 (6), 577-595; JP-A-5-208911]. In addition,involvement of EGF receptors in angiogenesis, which is closely relatedto metastasis of cancer, has been indicated [J. Biol. Chem., 1995, 912,895-898; Cancer Res., 1995, 55, 3772-3776]. Accordingly, apharmaceutical agent that inhibits tyrosine kinase is considered to beuseful not only as an agent for the prophylaxis or treatment of theabove-mentioned diseases but also as an anticancer agent having a newmechanism, which is applicable to many kinds of cancers and which causesfewer side effects. Various tyrosine kinase inhibitors have beenheretofore studied, and disclosed in JP-A-6-73025, JP-A-5-208911,Japanese Patent No. 2994165, JP-T-Hei 12-508657 and a recent paper byDiane H. Boschelli [Drugs of the Future 1999 24(5), 515-537], but havenot been put to practical use.

The four receptors of EGF receptor, HER2, ErbB3 and ErbB4 all belong tothe ErbB family, and these receptors form a heterocomplex and showinteraction in the intracellular signal transduction [J. Clin. Oncol.2001 19(18s), 32s-40s]. For example, it is known that coexpression ofEGF receptor and HER2 accelerates tumorigenesis solely derived from theEGF receptor [Cell 1987 58, 287-292]. There is a report that thecoexpression of EGF receptor and HER2 in breast cancer, oral cancer,lung cancer and the like causes poor prognosis [Clin. Cancer Res. 19995, 4164-4174]. Furthermore, there is a report that the coexpression ofEGF receptor and HER2 in breast cancer relates to the resistance toendocrine therapy [J. Steroid Biochem. 1989 34, 123-131].

The present invention aims at finding a pharmaceutical agent thatinhibits EGF receptor tyrosine kinase and a pharmaceutical agent thatinhibits both the EGF receptor tyrosine kinase and HER2 tyrosine kinase.The dual inhibitor of EGF receptor and HER2 is advantageous in that it:can be applied to a wider range of diseases and is superior in that thesynergistic dual inhibitory action affords a stronger treatment effectas compared to a pharmaceutical agent acting only on a single kinase.

The compound of the present invention shows a sustained enzymeinhibitory action and provides a more superior treatment effect than doconventionally reported reversible inhibitors.

DISCLOSURE OF THE INVENTION

The present inventors have conducted intensive studies with the aim ofsolving the above-mentioned problems and found that a quinazolinederivative having a particular structure has a strong tyrosine kinaseinhibitory activity and cancer cell growth inhibitory action, andreached the present invention.

Accordingly, the present invention provides the following.

(1) A quinazoline derivative of the following formula (I)

wherein

-   -   n is an integer of 0-3,    -   R¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano        group, a nitro group, a C₁-C₅ alkyl group, a C₁-C₅ alkoxy group,        —S(O)_(f)R¹³ (wherein f is an integer of 0-2 and R¹³ is a C₁-C₅        alkyl group), —NR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵ are each        independently a hydrogen atom, a C₁-C₅ alkyl group, a C₁-C₅        alkanoyl group or a C₁-C₅ alkylsulfonyl group), a C₂-C₅ alkenyl        group or a C₂-C₅ alkynyl group,    -   one of R² and R^(3 is R) ²⁷SO₂NH— wherein R²⁷ is a C₁-C₅ alkyl        group optionally substituted by a morpholino group, (R²⁸SO₂)₂N—        (wherein R²⁸ is a C₁-C₅ alkyl group optionally substituted by a        morpholino group), a C₁-C₅ alkoxy group, MeCOCH₂CONH—,        MeSCH₂CH₂CONH—, NCCH₂CONH—,

-   -   (wherein X is —C(O)— or SO₂— and R⁴, R⁵ and R⁶ are each        independently a hydrogen atom, a halogen atom or a C₁-C₅ alkyl        group optionally substituted by a halogen atom, a morpholino        group, a 4-C₁-C₅ alkylpiperazin-1-yl or di(C₁-C₅ alkyl) amino        group, or

-   -   (wherein R⁷ is a C₁-C₅ alkyl group optionally substituted by a        halogen atom, a morpholino group, 4-C₁-C₅ alkylpiperazin-1-yl or        di(C₁-C₅ alkyl) amino group, and    -   the other of R² and R³ is

-   -   wherein a) R⁸ and R⁹ are each independently a hydrogen atom, b)        R⁸ and R⁹ are each independently a C₁-C₅ alkyl group optionally        substituted by a hydroxyl group or a C₁-C₅ alkoxy group, c) R⁸        and R⁹ are taken together to show C═O or d) R⁸ and R⁹ in        combination form a ring to represent a C₃-C₈ cycloalkylene        optionally via —O—, —S— or —NR¹⁰ (wherein R¹⁰ is a hydrogen atom        or a C₁-C₅ alkyl group), m is an integer of 0-3, R¹¹ and R¹² are        each independently a hydrogen atom or a C₁-C₅ alkyl group, and Y        is a hydrogen atom, a hydroxyl group, a C₁-C₅ alkoxy group, a        C₁-C₅ alkanoyloxy group,        —N(R¹⁶)—(CO)_(u)—(CR¹⁷R¹⁸)_(v)—(CO)_(j)—R¹⁹ (wherein R¹⁶ is a) a        hydrogen atom or b) a C₁-C₅ alkyl group optionally substituted        by a cyano group or a C₁-C₅ alkoxy group, R¹⁷ and R¹⁸ are each        independently a hydrogen atom or a C₁-C₅ alkyl group, u and j        are each 0 or 1, v is an integer of 1-5 and R¹⁹ is a hydrogen        atom, a hydroxyl group, a cyano group, an amino group, a C₁-C₅        alkoxy group, a morpholino group, 4-C₁-C₅ alkylpiperazin-1-yl or        di(C₁-C₅ alkyl)amino group, provided that, when u and j are        simultaneously 0, then v is an integer of 2-5),

-   -   wherein p and q are each independently an integer of 2 or 3, Z        is —O— or —S(O)_(g)— wherein g is an integer of 0-2, a carbonyl        group or —NR²⁰— (wherein R²⁰ is a) a hydrogen atom, b) a C₁-C₅        alkylsulfonyl group, c) a C₁-C₅ alkanoyl group, d) a C₁-C₅        alkoxycarbonyl group or e) a C₁-C₅ alkyl group optionally        substituted by a cyano group, a hydroxyl group or a C₁-C₅ alkoxy        group) or

-   -   wherein r and t are each independently an integer of 1-3, k is 0        or 1, W is a hydrogen atom, a hydroxyl group, a C₁-C₅ alkoxy        group, a C₁-C₅ alkanoyloxy group, a carboxyl group, a cyano        group, a di(C₁-C₅ alkyl)amino group, a morpholino group,        pyrrolidin-1-yl, piperidin-1-yl, 4-C₁-C₅ alkylpiperazin-1-yl or        CONR²¹ R²² (wherein R²¹ and R²² are each independently a        hydrogen atom or a C₁-C₅ alkyl group),        or a pharmaceutically acceptable salt thereof, a hydrate        thereof, a solvate thereof, an optically active compound        thereof, a racemate thereof or a diastereomer mixture thereof.        (2) The quinazoline derivative of the aforementioned (1), which        is represented by the following formula (I)

wherein

-   -   n is an integer of 1 or 2,    -   R¹ is a halogen atom, a cyano group, a C₁-C₅ alkyl group, a        C₁-C₅ alkoxy group, —S(O)_(f)R¹³ (wherein f is an integer of 0-2        and R¹³ is a C₁-C₅ alkyl group), —NR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵        are each independently a hydrogen atom, a C₁-C₅ alkyl group, a        C₁-C₅ alkanoyl group or a C₁-C₅ alkylsulfonyl group) or a C₂-C₅        alkynyl group,    -   one of R² and R^(3 is R) ²⁷SO₂NH— (wherein R²⁷ is a C₁-C₅ alkyl        group optionally substituted by a morpholino group), (R²⁸SO₂)₂N—        (wherein R²⁸ is a C₁-C₅ alkyl group optionally substituted by a        morpholino group), a C₁-C₅ alkoxy group, MeCOCH₂CO—,        MeSCH₂CH₂CO—, NCCH₂CO—,

-   -   wherein X is —C(O)— or SO₂— and R⁴, R⁵ and R⁶ are each        independently a hydrogen atom, a halogen atom or a C₁-C₅ alkyl        group optionally substituted by a halogen atom, a morpholino        group, 4-C₁-C₅ alkylpiperazin-1-yl or di(C₁-C₅ alkyl)amino        group, or

-   -   wherein R⁷ is a C₁-C₅ alkyl group, and the other of R² and R³ is

-   -   wherein a) R⁸ and R⁹ are each independently a hydrogen atom, b)        R⁸ and R⁹ are each independently a C₁-C₅ alkyl group optionally        substituted by a C₁-C₅ alkoxy group, m is an integer of 0-3, R¹¹        and R¹² are each independently a hydrogen atom or a C₁-C₅ alkyl        group, and Y is a hydrogen atom, a hydroxyl group, a C₁-C₅        alkoxy group, a C₁-C₅ alkanoyloxy group,        —N(R¹⁶)—(CO)_(u)—(CR¹⁷R¹⁸)_(v)—(CO)_(j)—R¹⁹ (wherein R¹⁶ is a        hydrogen atom, or a C₁-C₅ alkyl group optionally substituted by        a cyano group or a C₁-C₅ alkoxy group, R¹⁷ and R¹⁸ are each        independently a hydrogen atom or a C₁-C₅ alkyl group, u andj are        each 0 or 1, v is an integer of 1-5 and R¹⁹ is a hydrogen atom,        a hydroxyl group, a cyano group, an amino group, a C₁-C₅ alkoxy        group, a morpholino group, 4-C₁-C₅ alkylpiperazin-1-yl or        di(C₁-C₅ alkyl)amino group,    -   provided that, when u and j are simultaneously 0, then v is an        integer of 2-5),

-   -   wherein p and q are each independently an integer of 2 or 3, Z        is —O—, a carbonyl group or —NR²⁰— (wherein R²⁰ is a hydrogen        atom, a C₁-C₅ alkylsulfonyl group, a C₁-C₅ alkanoyl group, a        C₁-C₅ alkoxycarbonyl group or a C₁-C₅ alkyl group optionally        substituted by a cyano group or a C₁-C₅ alkoxy group), or

-   -   wherein r and t are each independently an integer of 1-3, k is 0        or 1, W is a hydrogen atom, a hydroxyl group, a C₁-C₅ alkoxy        group, a C₁-C₅ alkanoyloxy group, a carboxyl group, a cyano        group, a di(C₁-C₅ alkyl)amino group, a morpholino group or        CONR²¹R²² (wherein R²¹ and R²² are each independently a hydrogen        atom or a C₁-C₅ alkyl group),        or a pharmaceutically acceptable salt thereof, a hydrate        thereof, a solvate thereof, an optically active compound        thereof, a racemate thereof or a diastereomer mixture thereof.        (3) The quinazoline derivative of the aforementioned (1) or (2),        which is represented by the following formula (I)

wherein

-   -   n is an integer of 0-3,    -   R¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano        group, a nitro group, a C₁-C₅ alkyl group, a C₁-C₅ alkoxy group,        —S(O)_(f)R¹³ (wherein f is an integer of 0-2 and R¹³ is a C₁-C₅        alkyl group), —NR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵ are each        independently a hydrogen atom, a C₁-C₅ alkyl group, a C₁-C₅        alkanoyl group or a C₁-C₅ alkylsulfonyl group), a C₂-C₅ alkenyl        group or a C₂-C₅ alkynyl group,    -   R² is

-   -   wherein X is —C(O)— or SO₂— and R⁴, R⁵ and R⁶ are each        independently a hydrogen atom, a halogen atom or a C₁-C₅ alkyl        group optionally substituted by a halogen atom, a morpholino        group, 4-C₁-C₅ alkylpiperazin-1-yl or di(C₁-C₅ alkyl)amino        group, or

-   -   wherein R⁷ is a C₁-C₅ alkyl group optionally substituted by a        halogen atom, a morpholino group, 4-C₁-C₅ alkylpiperazin-1-yl or        di(C₁-C₅ alkyl)amino group, and    -   R³ is

-   -   wherein R⁸ and R⁹ are each independently a hydrogen atom, a        C₁-C₅ alkyl group optionally substituted by a hydroxyl group or        a C₁-C₅ alkoxy group, R⁸ and R⁹ are taken together to denote C═O        or R⁸ and R⁹ combination form a ring to represent C₃-C₈        cycloalkylene optionally via —O—, —S— or —NR¹⁰ (wherein R¹⁰ is a        hydrogen atom or a C₁-C₅ alkyl group), m is an integer of 0-3,        R¹¹ and R¹² are each independently a hydrogen atom or a C₁-C₅        alkyl group, and Y is a hydrogen atom, a hydroxyl group, a C₁-C₅        alkoxy group, a C₁-C₅ alkanoyloxy group,        —N(R¹⁶)—(CO)_(u)—(CR¹⁷R¹⁸)_(v)—(CO)_(j)—R¹⁹ (wherein R¹⁶ is a        hydrogen atom, or a C₁-C₅ alkyl group optionally substituted by        a cyano group or a C₁-C₅ alkoxy group, R¹⁷ and R¹⁸ are each        independently a hydrogen atom or a C₁-C₅ alkyl group, u and j        are each 0 or 1, v is an integer of 1-5 and R¹⁹ is a hydrogen        atom, a hydroxyl group, a cyano group, an amino group, a C₁-C₅        alkoxy group, a morpholino group, 4-C₁-C₅ alkylpiperazin-1-yl or        a di(C₁-C₅ alkyl)amino group, provided that, when u and j are        simultaneously 0, then v is an integer of 2-5,

-   -   wherein p and q are each independently an integer of 2 or 3, Z        is —O— or —S(O)_(g)— (wherein g is an integer of 0-2), a        carbonyl group or —NR²⁰— (wherein R²⁰ is a hydrogen atom, or a        C₁-C₅ alkyl group optionally substituted by a cyano group or a        C₁-C₅ alkoxy group) or

-   -   wherein r and t are each independently an integer of 1-3, k is 0        or 1, W is a hydrogen-atom, a hydroxyl group, a C₁-C₅ alkoxy        group, a C₁-C₅ alkanoyloxy group, a carboxyl group, a cyano        group, a di(C₁-C₅ alkyl)amino group, a morpholino group,        pyrrolidin-1-yl, piperidin-1-yl, 4-C₁-C₅ alkylpiperazin-1-yl or        —CONR²¹R²² (wherein R²¹ and R²² are each independently a        hydrogen atom or a C₁-C₅ alkyl group),        or a pharmaceutically acceptable salt thereof, a hydrate        thereof, a solvate thereof, an optically active compound        thereof, a racemate thereof or a diastereomer mixture thereof.        (4) A compound of any of the aforementioned (1) to (3), which is        represented by the following formula (1a)

or a pharmaceutically acceptable salt thereof, a hydrate thereof, asolvate thereof, an optically active compound thereof, a racematethereof or a diastereomer mixture thereof.(5) The compound of the aforementioned (4), wherein the pharmaceuticallyacceptable salt is a salt with tosic acid.(6) A crystal of a salt of a compound of the following formula (1a)

with tosic acid.(7) The crystal of the aforementioned (6) having any one, two, three,four, five, six or all the characteristic absorbance peaks (2θ) shownbelow in powder X-ray diffraction pattern: characteristic peaks (2θ,±0.2°) 3.3°, 6.6°, 7.5°, 9.4°, 13.9°, 17.4°, 19.1°.(8) The compound of the aforementioned (4), wherein the hydrate is a ½hydrate.(9) A crystal of a ½ hydrate of a compound of the following formula (1a)

(10) The crystal of the aforementioned (9) having any one, two, three,four, five, six or all the characteristic absorbance peaks (2θ) shownbelow in powder X-ray diffraction pattern:characteristic peaks (2θ, ±0.2°) 7.1°, 10.6°, 11.9°, 12.2°, 13.8°,17.3°, 18.4°.(11) A pharmaceutical composition comprising a compound of any of theaforementioned (1) to (10) and a pharmaceutically acceptable carrier.(12) A tyrosine-specific protein kinase inhibitor comprising a compoundof any of the aforementioned (1) to (10) as an active ingredient.(13) The inhibitor of the aforementioned (12), wherein thetyrosine-specific protein kinase is EGF receptor tyrosine-specificprotein kinase.(14) The inhibitor of the aforementioned (12) or (13), wherein thetyrosine-specific protein kinase is EGF receptor tyrosine-specificprotein kinase and HER2 tyrosine-specific protein kinase.(15) An agent for the treatment and/or prophylaxis of a disease causedby potentiation of tyrosine-specific protein kinase activity, whichcomprises a compound of any of the aforementioned (1) to (10) as anactive ingredient.(16) The agent for the treatment and/or prophylaxis of theaforementioned (15), which is an anticancer agent, or for the treatmentand/or prophylaxis of psoriasis or a disease based on arteriosclerosis.

In the following, they are also simply referred to as a “tyrosine kinaseinhibitor” in the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an XRD pattern of compound 1a.½ H₂O type A crystal form.

FIG. 2 shows an XRD pattern of compound 1a.2TsOH type A crystal form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in detail in the following.

The compound of the present invention is a quinazoline derivative of theaforementioned formula (I).

As the halogen atom defined for each substituent of the aforementionedformula (I), fluorine atom, chlorine atom, bromine atom and iodine atomcan be mentioned; as the C₁-C₅ alkyl group, methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,sec-butyl group, tert-butyl group, n-pentyl group, neopentyl group andthe like can be mentioned; as the C₁-C₅ alkoxy group, methoxy group,ethoxy group, n-propoxy group, iso-propoxy group, n-butoxy group,iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxygroup, neopentyloxy group and the like can be mentioned; as the C₂-C₅alkenyl group, vinyl group, 1-propenyl group, 2-propenyl group,1-butenyl group, 2-methylpropen-1-yl group, 2-butenyl group, 1-pentenylgroup, 2-pentenyl group and the like can be mentioned; as the C₂-C₅alkynyl group, ethynyl group, 1-propynyl group, 1-butynyl group,1-pentynyl group and the like can be mentioned; and as the C₁-C₅alkanoylgroup, formyl group, acetyl group, propionyl group, butyryl group,isovaleryl group, valeryl group and the like can be mentioned.

The quinazoline derivative of the present invention is converted to asalt with the corresponding acid or base by a known method.

Examples of the salt include inorganic acid salts such as hydrochloride,sulfate, carbonate, phosphate and the like, and organic acid salts suchas formate, acetate, propionate, lactate, oxalate, fumarate, maleate,citrate, tartrate, benzoate, phthalate, methanesulfonate,p-toluenesulfonate, isethionate, glucuronate, gluconate and the like. Inaddition, alkali metal salts such as sodium salt, potassium salt and thelike, alkaline earth metal salts such as magnesium salt, calcium saltand the like, ammonium salt, a salt with a pharmacologically acceptableorganic amine (tetramethylamine, triethylamine, benzylamine,phenethylamine, monoethanolamine, diethanolamine,tris(hydroxyethylamine), lysine and arginine etc.) can be mentioned.

The quinazoline derivative of the present invention can have varioussteric structures. For example, when considered from an asymmetriccarbon atom as a center, the absolute configuration thereof may be(S)-form or (R)-form, or a racemate. Pure forms of optical isomer anddiastereoisomer, optional mixtures of the isomers, racemate and the likeare all encompassed in the present invention.

The quinazoline derivative of the formula (I) can be present in the formof, for example, a solvate such as hydrate or a non-solvate, and thepresent invention encompasses all such kinds of solvates having ananticancer activity.

Preferable embodiments of the compounds of the present invention areshown in the following Tables 1-9. In the Tables, Me means methyl group,Et means ethyl group and Pr means propyl group.

TABLE 1

Y¹

TABLE 2

Y¹

TABLE 3

Y² Y²

TABLE 4

Y²

TABLE 5

Y² Y²

TABLE 6

R²

TABLE 7

R²

TABLE 8

X¹

TABLE 9

Ar

Of the compounds represented by the aforementioned formula (I), acompound wherein one of R² and R³ has an amide bond can be produced by,for example, the following route (Scheme 1).

wherein each symbol is as mentioned above, R³¹ is bonded to one of the6-position and the 7-position of quinazoline ring, —NH₂ and —NO₂ arebonded to the other position, and other symbols are as defined above.

Compound (I) can be produced by a method wherein compound (I′) isreacted with the corresponding sulfonic acid chloride, sulfonic acidanhydride, acid chloride or acid anhydride in, for example, an aproticpolar solvent such as tetrahydrofuran (hereinafter to be referred to asTHF), an ether solvent such as diethyl ether and the like, a hydrocarbonsolvent such as toluene, heptane and the like, dimethylformamide(hereinafter to be referred to as DMF), dimethyl sulfoxide (hereinafterto be referred to as DMSO), acetonitrile and the like, a protic polarsolvent such as methanol, tert-butanol, water and the like or a mixedsolvent thereof, in the presence or absence of a 0 to 10 equivalentamount of a nitrogen-containing base such as triethylamine,diethylamine, pyridine, 4-(N,N-dimethylamino)pyridine (hereinafter to bereferred to as DMAP) and the like or an inorganic base such as sodiumcarbonate, potassium hydrogen carbonate and the like, at −20° C. to+200° C. for 5 min to 48 hrs. Alternatively, compound (I) can beproduced by condensation reaction of the corresponding sulfonic acid orcarboxylic acid in the co-presence of, for example, carbodiimides suchas dicyclohexylcarbodiimide and the like, and an activation agent suchas carbonyldiimidazole, diphenylphosphoryl azide and the like. Inaddition, a vinylsulfonamide compound can be produced by a treatment of2-haloethylsulfonyl halide and compound (I′) in the presence of anexcess of a base such as triethylamine and the like, or with a base; andan acetylacetamide compound can be produced by reacting compound (I′)with diketene in a solvent such as toluene, acetonitrile and the like.

While compound (I′) can be produced by reacting-the corresponding nitrocompound (I″) with a 1 to 50 equivalent amount of reduced iron, zincpowder, tin chloride and the like in an ether solvent such as THF,diethyl ether and the like, a hydrocarbon solvent such as toluene,heptane and the like, an aprotic polar solvent such as DMF, acetonitrileand the like, a protic polar solvent such as methanol, ethanol, waterand the like or a mixed solvent thereof, in the presence or absence of a0.1 to 10 equivalent amount of a mineral acid such as hydrochloric acid,sulfuric acid and the like or an organic acid such as acetic acid andthe like at a temperature of +20° C. to +200° C. for 5 min to 48 hrs, itmay be produced by a method comprising reaction with hydrazine in thepresence of a 0.1 to 10 equivalent amount of an iron salt such as FeCl₃and the like for 5 min to 48 hrs, or by a reduction method using a metalcomplex compound such as LiAlH₄, NaBH₄, NaAlH₂(OCH₂CH₂OMe)₂ and the likeor a metal hydride such as NaH and the like.

The compounds of the above-mentioned formulas (I′), (I″) and (I) can bealso produced by the following methods.

wherein P′ denotes amino group, nitro group, alkoxy group, or amidegroup such as sulfonamide, acrylamide and the like, Q denotes a leavinggroup such as halogen atom, trifluoromethanesulfonyl (OTf) and the like,P′ and Q are bonded to the 6-position or 7-position of quinazoline ring;M denotes hydrogen atom, Li, MgBr, SnR₃ or B(OR)₂; M′ denotes metal atom(group) such as Li, MgBr, SnR₃, AlR₂, B(OR)₂, ZrCp₂Cl wherein R ishydrogen atom or lower alkyl group and Cp is cyclopentadienyl group, andthe like or halogen atom such as Br, I and the like; and other symbolsare as defined above.

Compound (I′), (I″) or (I) can be produced by reacting compound (II′)with compound (III) or compound (III′) in, for example, an ether solventsuch as THF, diethyl ether and the like, a hydrocarbon solvent such astoluene and the like, an aprotic polar solvent such as DMF, dimethylsulfoxide, acetonitrile and the like, a protic polar solvent such asmethanol, tert-butanol, water and the like or a mixed solvent thereof,in the presence or absence of a 0 to 10 equivalent amount of anitrogen-containing base such as triethylamine, diethylamine, pyridineand the like or an inorganic base such as sodium carbonate, potassiumhydrogen carbonate, cesium fluoride and the like, a 0.001-0.5 equivalentamount of a palladium complex such as Pd(PPh₃)₄, Pd(OAc)₂, PdCl₂(PPh₃)₂and the like, a 0.001-0.5 equivalent amount of a copper compound such asCuI and the like at +20° C. to +200° C. for 5 mm to 48 hrs. In thiscase, acetylide (III) [M=Li, MgX (X is halogen atom)] prepared byreacting compound (III) (M=H) with alkyllithium such as butyllithium andthe like or a Grignard's reaction agent such as ethyl magnesium bromideand the like in an ether solvent such as THF, diethyl ether and thelike, or a hydrocarbon solvent such as benzene, toluene and the like maybe used. In addition, (III) [M=SnR₃, ZnCl, B(OR′)₂] wherein R is loweralkyl group and R′ is hydrogen atom or lower alkyl group, prepared by,for example, reaction with a trialkyltin chloride compound, zincchloride and a trialkoxyboron compound may be used. In the case of(III′) (M′=Br, I), a compound of the above-mentioned formula (I′), (I″)or (I) can be produced by placing this (III′) (M′=Br, I) and (II′) inthe co-presence of a 0.5-5 equivalent amount of hexamethylditin orbis(pinacolate)diboran in, for example, an ether solvent such as THF,diethyl ether and the like, a hydrocarbon solvent such as toluene andthe like, an aprotic polar solvent such as DMF, DMSO, acetonitrile andthe like, a protic polar solvent such as methanol, tert-butanol, waterand the like or a mixed solvent thereof, in the presence of a 0 to 10equivalent amount of a nitrogen-containing base such as triethylamine,diethylamine, pyridine and the like or an inorganic base such as sodiumcarbonate, potassium hydrogen carbonate, cesium fluoride and the like,and a 0.001-0.5 equivalent amount of a palladium complex such asPd(PPh₃)₄, Pd(OAc)₂, PdCl₂(PPh₃)₂, Pd/C and the like. It can be alsoproduced by lithiation of (III′) (M′=Br, I) with n-butyllithium,tert-butyllithium and the like in, for example, an ether solvent such asTHF, diethyl ether and the like or a hydrocarbon solvent such as tolueneand the like to give (III′) (M′=Li), which is then reacted with (II′)along with a 0.001-0.5 equivalent amount of a palladium complex such asPd(PPh₃)₄, Pd(OAc)₂, PdCl₂(PPh₃)₂ and the like.

For conversion of compound (II′) (P′=NO₂) to compound (II′) (P′=NH₂),the aforementioned reduction method of compound (I″) to (I′) can beused; and for conversion of (II′) (P′=NH₂) to (II′) (P′ is amide groupsuch as sulfonamide, acrylamide and the like), the aforementionedcondensation reaction of compound (I′) to (I) can be used.

Of the compounds represented by the above-mentioned formula (I), acompound wherein either R² or R³ is alkoxy group can be produced by thereaction of compound (II′) (P′ is C₁-C₅ alkoxy group) with compound(III) or compound (III′) (Scheme 2).

Of the compounds represented by the above-mentioned formula (I′) and(I″), a compound wherein R³ is represented by

wherein Y, R⁸, R⁹, R¹¹, R¹² and m are as defined above, can be obtainedby subjecting, from among the compounds of the above-mentioned formula(I′) and (I″), a compound wherein R³ is

wherein Y, R⁸, R⁹, R¹¹, R¹² and m are as defined above, to reduction bycatalytic hydrogenation using a 0.0001-0.5 equivalent amount ofPd/BaSO₄, PtO₂, Pd/C and the like as a catalyst in, for example, anether solvent such as THF, diethyl ether and the like, a hydrocarbonsolvent such as toluene and the like, halogenated hydrocarbon such asdichloromethane and the like, an aprotic polar solvent such as DMF,acetonitrile and the like, a protic polar solvent such as methanol,tert-butanol, water and the like or a mixed solvent thereof, or by, forexample, hydrometallation reaction using a 0.1-5 equivalent amount ofLiAlH₄, (i-Bu)₂AlH, diboran, followed by hydrolysis.

Now the production methods of compounds (III) and (III′) are givenbelow.

Compound (III′) can be produced by, for example, hydrometallationreaction using, for example, LiAlH₄, (i-Bu)₂AlH, R₃SnH, Cp₂Zr(H)Cl,Cp₂TiCl₂—RMgX (Cp is cyclopentadienyl group, R is lower alkyl group andX is halogen atom) of the corresponding acetylene compound (III) (M=H)in an ether solvent such as THF, diethyl ether and the like, ahydrocarbon solvent such as toluene and the like, an aprotic polarsolvent such as DMF, acetonitrile and the like or a mixed solventthereof, or without a solvent, at a temperature of −30° C. to +150° C.By capturing compound (III′) with, for example, a halogenating agentsuch as iodine, N-iodosuccinimide, N-bromosuccinimide and the like, thecompound can be converted to compound (III′) (M′=Br, I).

wherein R²³ denotes

wherein each symbol is as mentioned above, and X¹ and X² aresimultaneously, or one of X¹ and X² is, bromine atom or chlorine atom.

Compound (III) (M=H) can be produced by, for example, a method shown inScheme 3. That is, haloalkene can be produced by a method comprisingoxidization of the corresponding alcohol to give aldehyde and reactionthereof with, for. example, a 0.1 to 10 equivalent amount each of carbontetrachloride and triphenylphosphine in a suitable solvent such asdichloromethane, carbon tetrachloride and the like at −20 to +50° C. for5 min to 48 hrs, or a method comprising reaction of, for example,(EtO)₂P(O)CCl₃ with an organic lithium compound such as n-butyllithiumand the like in a solvent such as THF, diethyl ether and the like or amixed solvent thereof at −100° C. to +100° C. for 5 min to 48 hrs, andthe resulting haloalkene is treated with an organic lithium compoundsuch as n-butyllithium and the like in, for example, a solvent such asTHF, diethyl ether and the like or a mixed solvent thereof at −100° C.to +100° C. for 5 min to 48 hrs, and then hydrolyzed to give compoundIII. Where necessary, this conversion is carried out after protection offunctional group in the compound.

wherein R²⁴ denotes hydrogen atom or trialkylsilyl group, M₁ denotes ametal atom (group) such as Li, MgBr or CeCl₃ and the like, R²⁷ denoteshydrogen atom, C₁-C₅ aikyl group or C₁-C₅ alkanoyl group, R²⁵ and R²⁶each denote R¹⁶—(CR¹⁷R¹⁸)_(v)—(CO)_(j)—R⁹ wherein each symbol is asmentioned above, or R²⁵ and R²⁶ are taken together to form a ring,

wherein each symbol is as mentioned above, or

wherein each symbol is as mentioned above.

Particularly, for the production of compound (III) (m=0, M=H, Y are asdefined above, except Y═H) (Scheme 4), an alcohol compound (III)(m=0,M=H, Y═OH) can be produced by reacting the corresponding ketone oraldehyde with ethynyl magnesium halide, lithium trimethylsilylacetylideor an ethynylation agent such as ethynylcelium compound and the likeproduced by reacting these with, for example, CeCl₃, in a suitablesolvent such as THF, diethyl ether, toluene and the like at −100° C. to+100° C. for 5 min to 48 hrs. An acylated compound or an ether compound(III) (m=0, M=H, Y═C₁-C₅ alkoxy group, or C₁-C₅ alkanoyl group) can beproduced by reacting the alcohol compound with an acid anhydride such asacetic anhydride and the like, an acylating agent such as acid chloride(e.g., acetic acid chloride and the like) and the like or an alkylationagent such as alkyl halide, alkylmethanesulfonate and the like in asuitable solvent such as dichloromethane, toluene, acetonitrile and thelike in the presence of a base such as pyridine, triethylamine and thelike or a base also as a solvent at 0° C. to 150° C. for 5 min to 48hrs. Here, a method wherein ketone is reacted with an ethynylation agentand, without isolating the alcohol compound, alkoxide generated in situis directly captured by an acylating agent or alkylating agent such asacid anhydride, acid chloride and the like, can be also used. Inaddition, the acylated compound can be produced by a method wherein thealcohol compound is reacted with an acid anhydride or an acid chloridein a suitable solvent such as acetonitrile, toluene, THF and the like inthe presence of a 0.0001 to 0.5 equivalent amount of a suitable Lewisacid such as Sc(OTf)₃ and BF₃.OEt₂ at −30° C. to 120° C. When lithiumtrimethylacetylide is used, a treatment for removal of trimethylsilylaccording to a conventional method may be performed before or after theacylation step or etheration step as necessary.

By reacting the acylated compound with the corresponding amine in, forexample, a suitable solvent such as THF, dichloromethane, toluene,acetonitrile and the like, in the presence of a 0.001 equivalent amountto 0.5 equivalent amount of copper compound such as CuCl, CuI or copperpowder and the like at 0° C. to +100° C. for 5 min to 48 hrs, (III){m=0, M=H, Y═NR²⁵R²⁶ wherein NR²⁵, R²⁶ are as defined above} can beproduced. By a method wherein (III) {m=0, M=H, Y═NHR¹⁶ wherein R¹⁶ areas defined above}, which can be produced by the above method, is reactedwith the corresponding carboxylic acid chloride or acid anhydride in anether solvent such as THF, diethyl ether and the like, a hydrocarbonsolvent such as toluene, heptane and the like, an aprotic polar solventsuch as DMF, dimethyl sulfoxide, acetonitrile and the like, a proticpolar solvent such as methanol, tert-butanol, water and the like or amixed solvent thereof, in the presence or absence of a 0 to 10equivalent amount of a nitrogen-containing base such as triethylamine,diethylamine, pyridine, DMAP and the like or an inorganic base such assodium carbonate, potassium-hydrogen carbonate and the like at −20° C.to +200° C. for 5 min to 48 hrs, or a method wherein (III) is subjectedto a condensation reaction with the corresponding carboxylic acid in theco-presence of, for example, carbodiimides such asdicyclohexylcarbodiimide and the like, and a condensation agent such ascarbonyldiimidazole, diphenylphosphorylazide and the like, (III) {m=0,M=H, Y═N(R¹⁶)—(CO) (CR¹⁷R¹⁸)_(v)—(CO)_(j)—R¹⁹ wherein R¹⁶ to R¹⁹, j andv are as defined above} can be produced.

In the case of production of compound (III) (m=1 to 3, M=H, Y═—NR²⁵R²⁶;R²⁵, R²⁶ are as defined above, except Y═H), from among the correspondingcompounds (III), a compound wherein Y is halogen atom such as chlorine,bromine, and the like, or a leaving group such as toluenesulfonate,methanesulfonate and the like is reacted with a 0.5-100 equivalentamount of the corresponding amine in a suitable solvent such asacetonitrile, THF, DMF and the like, in the presence or absence of abase such as potassium carbonate, diisopropylethylamine, sodium hydrideand the like, at −20° C. to +150° C. for 5 min to 72 hrs to give (III){m=1 to 3, M=H, Y═NR²⁵R²⁶ wherein NR²⁵, R²⁶ are as defined above}. Bysubjecting III) {m=1 to 3, M=H, Y═NHR¹⁶ wherein R¹⁶ is as defined above}produced by this method to a condensation reaction similar to that usedfor the above-mentioned (III) {m=0, M=H, Y═NHR¹⁶ wherein R¹⁶ are asdefined above}, compound (III) {m=1 to 3, M=H, Y═N(R¹⁶)—(CO)(CR¹⁷R¹⁸)_(v)—(CO)_(j)—R¹⁹ wherein R¹⁶ to R¹⁹, j and v are as definedabove} can be produced.

The quinazoline derivative of the present invention can be used as anagent for treatment and/or prophylaxis of the diseases caused bypotentiation of tyrosine kinase activity; that is, as an anticanceragent or an agent for the treatment and/or prophylaxis of psoriasis andthe diseases (e.g., ischemic cardiac disease, acute coronary arterysyndrome etc.) based on arteriosclerosis action.

When the compound of the present invention represented by theabove-mentioned formula (I) is used for the above-mentioned objects, itis generally administered systemically or topically in an oral orparenteral form. The dose varies depending on the age, body weight,symptom, treatment effect, administration method, treatment period andthe like. Generally, the compound is orally administered to an adult inan amount of 1 mg to 5 g per dose, once to several times a day, orparenterally administered to an adult in an amount of 1 mg to 5 g perdose, once to several times a day, or intravenously administered in asustained manner for 1 hr to 24 hrs a day. Because the dose variesdepending on diverse conditions as mentioned above, a dose less than theabove-mentioned dose may be sufficient, or administration of a dosebeyond the above dose range may be necessary.

When the compound of the present invention is administered, it is usedas a solid composition, liquid composition or other composition for oraladministration, an injection for parenteral administration, an externalagent, an adhesive plaster, a suppository and the like. The compound canbe administered alone, or as a part of a pharmaceutically acceptablecomposition containing a pharmaceutically acceptable-excipient. It isalso possible to administer simultaneously or sequentially one or morekinds of the compounds of the aforementioned formula (I).

Solid compositions for oral administration include tablet, pill,capsule, powder, granule and the like. Capsules include hard capsule andsoft capsule. In such a solid composition, one or more active substancesare admixed with at least one inert diluent, such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinyl pyrrolidone and metamagnesium silicate aluminate. Thecomposition may contain an additive other than the inert diluent, suchas lubricant (e.g., talc, magnesium stearate, solid polyethylene glycol,sodium lauryl sulfate), disintegrant (e.g., calcium celluloseglucolate), stabilizer (e.g., lactose) and dissolution aids (e.g.,glutamine acid, aspartic acid), according to a conventional method.Tablet and pill may be coated with a film of a gastric-soluble orenteric substance as necessary, such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and the like, or maybe coated with two or more layers. Furthermore, capsules made from anabsorbable substance such as gelatin are also encompassed.

Liquid compositions for oral administration include pharmaceuticallyacceptable solution, emulsifier, suspension, syrup, elixir and the like,and may contain inert diluent generally used, such as water and othersolvents, solubilizing agent and emulsifier, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylen e glycol,dimethylformamide, cottonseed oil, Apios americana oil, corn germ oil,olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfurylalcohol, polyethylene glycol and sorbitan fatty acid ester, a mixture ofthese substances and the like. Besides these inert diluents, thecomposition may contain an aid such as wetting agent and suspendingagent, sweetener, flavoring agent, fragrance agent and preservative.

A suspension may contain, besides the active compound, suspending agentsuch as ethoxyl isostearyl alcohol, polyoxyethylenesorbitol and sorbitanester, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar and tragacanth, a mixture of these substances and the like.

Other composition for oral administration contains one or more activesubstances, and includes a spray agent formulated according to a methodknown per se. This composition may contain, other than an inert diluent,a stabilizer such as sodium hydrogensulfite and a buffer affordingisotonicity, such as sodium chloride, sodium citrate and citric acid.The production method of the spray agent is described in, for example,U.S. Pat. Nos. 2,868,691 and 3,095,355.

The composition for injection of the present invention for parenteraladministration includes physiologically acceptable sterilized aqueous ornonaqueous solution, suspension and emulsifier. The aqueous solution andsuspension are exemplified by distilled water for injection andphysiological saline. As the water-insoluble solution and suspension,for example, propylene glycol, polyethylene glycol, olive oil, ethanol,polysorbate 80 and the like can be mentioned. Such compositions maycontain an aid such as preservative, wetting agent, emulsifier,dispersing agent, stabilizer (e.g., lactose) and dissolution aids (e.g.,glutamic acid, aspartic acid). These are sterilized by, for example,filtration through a bacteria retention filter, addition of sterilizingagent or irradiation. It is also possible to produce a sterilized solidcomposition, which is dissolved in sterilized water or sterilizedsolvent for injection, before use of, for example, a lyophilizedproduct.

Other compositions for parenteral administration include externalliquid, ointment, liniment, suppository, pessary and the like, whichcontain one or more active substances and are prescribed by conventionalmethods.

EXAMPLES

The present invention is explained in detail in the following byreferring to Synthetic Examples and Examples, which are not to beconstrued as limitative as long as they are within the scope of thepresent invention. In the following, unless particularly indicated, eachoperation means the following.

1) The reaction operation was performed at an ambient temperature, or18-25° C., in an inert gas, for example, under a nitrogen atmosphere.

2) The concentration was done using a rotary evaporator under reducedpressure, and drying was done on, for example, anhydrous sodium sulfate,and desiccant was removed by filtration.

3) For purification, for example, recrystallization, suspension-washingcomprising stirring in a suspension state, sublimation, or columnchromatography (by flushing method) was used. For column chromatography,a suitable developer, such as chloroform-methanol and the like, wasused.4) The structure of the objective product of the aforementioned formula(I) was confirmed by proton (¹H or 1H) nuclear magnetic resonance (NMR)(300 MHz or 270 MHz, 300 MHz unless particularly specified) and/or massspectrum: ¹H NMR was measured in deuterated dimethyl sulfoxide (DMSO-d₆,DMSO-d₆) or deuterated chloroform (CDCl₃, CDCl₃) unless particularlyspecified, chemical shift value is expressed by delta values (δ ppm)based on tetramethylsilane (TMS), and the peak multiplicity is expressedaccording to the following: s, singlet; d, doublet; t, triplet; q,quartet; m, multiplet; br, broad peak.5) The following abbreviations were used: n-hexane (Hex or hexane); Acacetyl group; Ms methanesulfonyl group; Tf trifluoromethanesulfonylgroup; EDC 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride.6) Powder X-ray diffraction pattern was measured according to thefollowing conditions.

-   -   Diffractometer: PHILIPS PW1700    -   Target: Cu    -   Monochro.: Graphite    -   Tube Voltage: 40 kV    -   Tube Current: 30 mA    -   Divergence Slit: 1°    -   Receiving Slit: 0.2 mm    -   Scatter Slit: 1°    -   Range: 3-40° 2θ

Synthetic Example 1 1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (4a)

A solution of acetic acid 1,1-dimethyl-2-propynyl ester(2-methyl-3-butyn-2-yl acetate) (51.5 g, 408.2 mmol), copper chloride(I) (2.02 g, 20.4 mmol), triethylamine (56.6 mL, 408.2,mmol) and1-methylpiperazine (54.3 mL, 489.9 mmol) in THF (480 mL) was reactedunder reflux for 2 hrs. The reaction mixture was concentrated, andtert-butylmethyl ether (200 mL) was added to the residue. The productwas extracted with dilute hydrochloric acid. 6N Aqueous sodium hydroxidesolution was added to the extract with stirring under ice-cooling untilthe aqueous layer showed basicity, and the mixture was extracted withdichloromethane (500 mL×1, 150 mL×3). The extracts were washed with 14%aqueous ammonia, and then with saturated brine, dried and concentrated.The resulting brown solid was purified by sublimation (60° C./5-6 Torr)to give the title compound as colorless crystals (49.07 g, 72%).

4a: ¹H NMR (CDCl₃) δ ppm: 1.40 (s, 6H), 2.28 (s, 1H), 2.28 (s, 3H), 2.49(br s, 4H), 2.69 (br s, 4H).

Synthetic Example 2N⁴-(3-chloro-4-fluorophenyl)-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-4,6-quinazolinediamine(2a)

1) A mixture (about 3:1, 52.0 g; described in Leonard et al., J. Org.Chem. 1975, 40, 356-363) of 7-chloro-6-nitro-3H-quinazolin-4-one and7-chloro-8-nitro-3H-quinazolin-4-one and DMF (0.7 mL) were added tothionyl chloride (200 mL) and the mixture was heated under reflux for 4hrs. The reaction mixture was concentrated to dryness and toluene (150mL) was added. The mixture was concentrated further. This step wasrepeated twice and dichloromethane (280 mL) was added to the residue.The mixture was stirred at room temperature. To this suspension wasadded dropwise a solution (760 mL) of 3-chloro-4-fluoroaniline (36.9 g,253.6 mmol) in isopropanol. Dichloromethane (300 mL) was added and themixture was stirred, at 20° C. for 20 min. Hexane (600 mL) was addedunder ice-cooling, and stirring was continued at 20° C. The precipitatewas collected by filtration, washed with hexane (200 mL×2) and driedunder reduced pressure. The obtained solid was added to methanol (1L)-water (120 mL), and triethylamine (30 mL) was added with stirringunder ice-cooling. After stirring at room temperature for 1 hr, theprecipitate was collected by filtration and washed with water (700mL×2). The crudely purified substance (65 g) was suspension-washed withacetonitrile (1.2 L) with heating, and collected by filtration to givethe objective(7-chloro-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (54.6g, 67%).2) Nitrogen was passed through a solution (70 mL) of(7-chloro-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (14.2g. 40.1 mmol), 1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (4a) (10.0g, 60.1 mmol), copper iodide (I) (380 mg), andtetrakis(triphenylphosphine)palladium (1.39 g) in DMF at 50° C. for 15mm and triethylamine (13.9 mL, 100.0 mmol) was added and the mixture wasstirred at an oil bath temperature of 140° C. for 50 mm. The reactionmixture was allowed to cool and concentrated. Aqueous sodium hydrogencarbonate (300 mL) was added, and the product was extracted with ethylacetate (200 mL×2), dried and concentrated. The residue was subjected tosilica gel column chromatography (chloroform-methanol; ethylacetate-methanol) to give the objective nitro compound of(3-chloro-4-fluorophenyl)-{7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-nitro-4-quinazolinyl}amine(3a) (7.25 g, 37%).

3a: ¹H NMR (CDCl₃) δ ppm: 1.54 (s, 6H), 2.28 (s, 3H), 2.53 (s, 4H), 2.82(s, 4H), 7.21 (t, J=8.7 Hz, 1H), 7.59 (m, 1H), 7.99 (m, 1H), 8.08 (s,1H), 8.80 (s, 1H), 8.81 (s, 1H).

3) A suspension of nitro compound 3a (3.69 g, 7.64 mmol), acetic acid (5mL) and iron powder (1.71 g, 30.6 mmol) in ethanol (100 mL)-water (50mL) was refluxed for 20 mm. 10% Aqueous sodium carbonate solution (90mL) was added to the reaction mixture under ice-cooling, and the mixturewas stirred at room temperature for 1 hr and filtered through Celite.The residue was washed with ethanol (150 mL×3) and the filtrate wasconcentrated. Water (100 mL) was added and the precipitate was collectedby filtration. The product was washed with water and dried under reducedpressure to give the objective amino form,N⁴-(3-chloro-4-fluorophenyl)-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-4,6-quinazolinediamine(2a) (3.02 g, 87%).

2a: ¹H NMR (CDCl₃) δ ppm: 1.55 (s, 6H), 2.30 (s, 3H), 2.53 (br s, 4H),2.80 (br s, 4H), 4.53 (br s, 2H), 6.93 (s, 1H), 7.11, (s, 1H), 7.17 (t,J=8.8 Hz, 1H), 7.53 (m, 1H), 7.88 (s, 1H), 7.93 (dd, J=2.5, 6.5 Hz, 1H),8.58 (s, 1H).

Synthetic Example 3(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine

1) A solution (250 mL) of 2,5-dibromo-1-nitrobenzene (4.32 g, 15.4 mmol)in THF was cooled to −105° C. and 0.88 M phenyllithium/THF solution(19.8 mL, 17.4 mmol) was slowly added dropwise. After 30 min, DMF (5.4mL, 69.6 mmol) was slowly added dropwise and the temperature was slowlyraised to −20° C. Dilute aqueous sulfuric acid solution (100 mL) wasadded to the reaction mixture and the mixture was concentrated. Theproduct was extracted with ethyl acetate (80 mL×2). The organic layerwas dried, concentrated and the resulting brown solid (5.66 g) wasdissolved in acetone (50 mL). Jone's reagent (20 mL) was slowly added tothis solution under ice-cooling, and the temperature was slowly raisedto room temperature. Isopropanol was added to the reaction mixture andthe mixture was concentrated. 2 mol/L Aqueous sodium hydroxide solution(100 mL) was added and the mixture was filtered. Concentratedhydrochloric acid was added to acidify the filtrate. The precipitate wascollected by filtration and the residue was washed with water and driedto give 4-bromo-2-nitrobenzoic acid (1.95 g, 52%).

¹H NMR (DMSO-d₆) δ ppm: 7.80 (br s, 1H), 7.98 (br s, 1H), 8.25 (br s,1H), 14.1 (br s, 1H).

2) To 4-bromo-2-nitrobenzoic acid (1.80 g, 7.83 mmol) were added 0.88Naqueous sodium hydroxide solution (10 mL), iron(III) chloride (133 mg)and isopropyl alcohol (0.7 mL) and the mixture heated to 75° C. Whilestirring the mixture, hydrazine (1.1 mL) was slowly added, and themixture was reacted at 75° C. for 2 hrs. The reaction mixture wasfiltered and the filtrate was concentrated. The precipitated solid waswashed with water to give 4-bromoanthranilic acid (1.73 g, 96%).

¹H NMR (DMSO-d₆) δ ppm: 6.62 (dd, J=1.5, 8.5 Hz, 1H), 6.95 (d, J=1.5 Hz,1H), 7.56 (d, J=8.5 Hz, 1H).

3) Formamidine acetate (1.96 g, 18.9 mmol) and 2-ethoxyethanol (25 mL)were added to 4-bromoanthranyl acid (1.63 g, 7.55 mmol) and the mixturewas heated under reflux for 7 hrs. Formamidine acetate (1.45 g) wasadded and the mixture was further refluxed for 6 hrs. Dilute aqueousammonia solution (30 mL) was added, and after stirring for a while, theproduct was collected by filtration and dried to give the objective7-bromo-3H-quinazolin-4-one (1.67 g, 98%).

¹H NMR (DMSO-d₆) δ ppm: 7.69 (dd, J=1.9, 8.4 Hz, 1H), 7.89 (d, J=1.9 Hz,1H), 8.04 (d, J=8.4 Hz, 1H), 8.14 (br s, 1H).

To a mixed solution of concentrated sulfuric acid (3 mL) and fumingnitric acid (3 mL) was added 7-bromo-3H-quinazolin-4-one (1.67 g, 7.42mmol), and the mixture was heated at an oil bath temperature of 95° C.to 100° C. for 1 hr. The reaction mixture was poured into water (50 mL),and the product was collected by filtration, washed with water and driedunder reduced pressure to give an about 5.6:1 mixture (1.3 g, 65%) ofthe objective 7-bromo-6-nitro-3H-quinazolin-4-one and7-bromo-8-nitro-3H-quinazolin-4-one.

7-bromo-6-nitro-3H-quinazolin-4-one

¹H NMR (DMSO-d₆) δ ppm: 8.15 (s, 1H), 8.27 (s, 1H), 8.61 (s, 1H).

This mixture (1.26 g) was converted to(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (1.38 g,74%) in the same manner as in Synthetic Example 2-1).

(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine

¹H NMR (DMSO-d₆) δ ppm: 7.46 (t, J=9.2 Hz, 1H), 7.77 (m, 1H), 8.13 (m,1H), 8.25 (s, 1H), 8.73 (s, 1H), 9.33 (s, 1H), 10.37 (br s, 1H).

Synthetic Example 4(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride

1) To a solution of 2,5-dibromonitrobenzene (80 g, 285 mmol) in DMF (500mL) was added copper cyanide (I) (38 g, 427 mmol) and the mixture wasstirred at 100° C. for 1.5 hrs. The reaction mixture was allowed toreach room temperature and toluene (750 mL)-water (1250 mL) was added.Then, Celite (50 g) was added, and after thorough stirring, insolublematerial was filtered off. The filtrate was partitioned and the organiclayer was washed successively with water (500 mL), 1% aqueous ammonia(250 mL×2), water (250 mL) and saturated brine (500 mL), and dried overanhydrous sodium sulfate, after which the solvent was evaporated underreduced pressure to give a yellow solid (61.4 g) containing2-cyano-5-bromonitrobenzene as a main component. This was dissolved inethyl acetate (270 mL) and platinum oxide monohydrate (330 mg, 1.35mmol) was added. The inside of the reaction container was displaced withhydrogen and the mixture was stirred under a hydrogen atmosphere for41.5 hrs. Insoluble material was filtered off and the residue was washedwith ethyl acetate (200 mL) and then with ethanol (100 mL). The filtratewas evaporated under reduced pressure, and after drying, suspended inether (250 mL). The suspension was stirred with heating under reflux.The mixture was allowed to cool to room temperature and the insolublematerial was collected by filtration to give 4-bromoanthranilic amide(40 g, 186 mmol, 65%).

2-cyano-5-bromonitrobenzene

¹H NMR (DMSO-d₆) δ ppm: 8.10 (d, J=8.3 Hz, 1H), 8.21 (dd, J=1.8, 8.3 Hz,1H), 8.57 (d, J=1.8 Hz, 1H)

4-bromoanthranilic amide

¹H NMR (DMSO-d₆) δ ppm: 6.61 (dd, J=1.8, 8.4 Hz, 1H), 6.81 (br s, 2H),6.89 (d, J=1.8 Hz), 7.17 (br s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.79 (br s,1H).

2) 4-Bromoanthranilic amide (40 g, 186 mmol) obtained in 1) wasdissolved in ethanol (400 mL). Thereto was added sodium methoxide (54.2g, 93 mmol) with stirring under ice-cooling and then ethyl formate (60.1mL, 744 mmol) was added dropwise. The mixture was heated under refluxfor 1.5 hrs. The reaction mixture was allowed to cool to roomtemperature and water (500 mL) was added and then acetic acid (40 mL)was added. The mixture was concentrated under reduced pressure and water(200 mL) was added. The precipitate was collected by filtration anddried to give 7-bromo-3H-quinazolin-4-one (35 g, 156 mmol, 84%).

7-bromo-3H-quinazolin-4-one

¹H NMR (DMSO-d₆) δ ppm: 7.68 (dd, J=1.7, 8.5 Hz, 1H), 7.88 (d, J=1.7 Hz,1H), 8.03 (d, J=8.5 Hz, 1H), 8.14 (s, 1H).

3) 7-Bromo-3H-quinazolin-4-one (35 g, 156 mmol) obtained in 2) wasdissolved in sulfuric acid (56 mL) and stirred on an oil bath at 90° C.Thereto was added dropwise fuming nitric acid (56 mL) by small portionswhile maintaining the temperature of the reaction mixture at not higherthan 120° C. After the completion of the dropwise addition, the mixturewas further stirred with heating at 90° C. for 1 hr. The reactionmixture was allowed to cool to room temperature and poured into icewater (1.5 L). The precipitated solid was collected by filtration andwashed with water (500 mL). Drying gave a mixture (about 3:1, 37 g) of7-bromo-6-nitro-3H-quinazolin-4-one and7-bromo-8-nitro-3H-quinazolin-4-one. Thereto was added thionyl chloride(205 mL) and DMF (2.5 mL) and the mixture was heated under reflux for 2hrs. The reaction mixture was concentrated to dryness under reducedpressure. Thereto was added dichloromethane (370 mL) and a solution of3-chloro-4-fluoroaniline (21.9 g, 151 mmol) in isopropanol (1.1 L) wasadded dropwise with stirring at room temperature. The mixture wasfurther stirred for 4 hrs. Hexane (1.1 L) was added to the reactionmixture and the precipitate was collected by filtration. Drying gave(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride (42.7 g, 98.4 mmol, 72%).

(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride

¹H NMR (DMSO-d₆) δ ppm: 7.52 (t, J=9.0 Hz, ,1H), 7.81 (m, 1H), 8.15 (m,1H), 8.33 (s, 1H), 8.86 (s, 1H), 9.54 (s, 1H), 11.16 (br s, 1H).

4) A solution of(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride (42.0 g, 96.8 mmol),1-(1,1-dimethyl-2-propynyl)-4-methylpiperazine (4a) (19.3 g, 116 mmol)and triethylamine (47.2 mL, 339 mmol) in DMSO (400 mL) was subjected 3times to the step of degassing under reduced pressure and thendisplacement with nitrogen. Copper iodide (I) (460.8 mg, 2.4 mmol),triphenylphosphine (2.53 g, 9.6 mmol) and palladium(II) acetate (543 mg,2.4 mmol) were added. The mixture was stirred at 80° C. for 9 hrs andallowed to cool to room temperature. The mixture was poured into ethylacetate (750 mL) and 1% aqueous ammonia solution (1.5 L), and Celite (50g) was added, which was followed by stirring. Insoluble material wasfiltered off and the organic layer was washed with brine (500 mL×2) anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and ethyl acetate-methanol mixed solvent (10:1, 130 mL)was added to the residue. The mixture was stirred and the precipitatewas collected by filtration. The filtered product was suspension-washedwith acetonitrile (100 mL) and dried to give a nitro compound 3a (23.3g, 48.3 mmol, 50%).

Example 1

A solution of the amino compound 2a (6.08 g, 13.4 mmol) obtained by themethod of Synthetic Example 2, acrylic acid (1.38 mL, 20.1 mmol),triethylamine (2.8 mL, 20.1 mmol) and EDC (3.86 g, 20.1 mmol) in DMF(100 mL) was stirred overnight at room temperature. Acrylic acid (0.46mL, 6.71 mmol), triethylamine (0.93 mL, 6.71 mmol) and EDC (1.29 g, 6.71mmol) were added to the reaction mixture and the mixture was furtherstirred overnight. The reaction mixture was poured into aqueous sodiumhydrogen carbonate (300 mL) and the mixture was filtered. The residuewas washed with water and water-ethanol and dried. The crudely purifiedsubstance was stirred with heating in water-ethanol and cooled to roomtemperature. The precipitate was collected by filtration and dried togive the objective compound 1a (3.41 g, 50%).

1a: ¹H NMR (DMSO-d₆) δ ppm: 1.44 (s, 6H), 2.15 (s, 3H), 2.35 (br s, 4H),2.64 (br s, 4H), 5.85 (d, J=10.3 Hz, 1H), 6.33 (d, J=16.9 Hz, 1H), 6.58(dd, J=10.3, 16.9 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 7.84 (br s, 2H), 8.20(br d, J=6.1 Hz, 1H), 8.64 (s, 1H), 8.69 (s, 1H), 9.88 (s, 1H), 10.01(s, 1H).

Example 2

In the same manner as in Synthetic Example 2-2) 3) and using(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine obtainedby the method of Synthetic Example 3 and1-(1,1-dimethyl-2-propynyl)morpholine (4b), amino compound 2b wasobtained. In the same manner as in Example 1, compound 1b was obtainedfrom compound 2b.

Note that 4b used for the reaction was produced in the same manner as inSynthetic Example 3 using morpholine instead of 1-methylpiperazine.

1b (yield 87%): ¹H NMR (DMSO-d₆) δ ppm: 1.43 (s, 6H), 2.61 (m, 4H), 4.18(m, 4H), 5.84 (d, J=10.2 Hz, 1H), 6.33 (d, J=16.9 Hz, 1H), 6.56 (dd,J=10.2, 16.9 Hz, 1H), 7.44 (t, J=9.1 Hz, 1H), 7.80-8.00 (m, 2H), 7.95(m, 1H), 8.60-8.70 (m, 2H), 9.85-9.90 (m, 2H).

2b (yield 79%): ¹H NMR (DMSO-d₆) δ ppm: 1.47 (s, 6H), 2.64 (m, 4H), 3.65(m, 4H), 5.55 (m, 2H), 7.43 (t, J=9.2 Hz), 7.52 (s, 1H), 7.65 (s, 1H),7.82 (m, 1H), 8.20 (m 1H), 8.39 (m 1H), 9.64 (s, 1H).

4b (yield 73%): ¹H NMR (DMSO-d₆) δ ppm: 1.39 (s, 6H), 2.31 (s, 1H), 2.64(t, J=4.7 Hz, 4H), 3.75 (t, J=4.7 Hz, 4H).

Synthetic Example 57-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine (5)

Reduced iron (84.2 g, 1.51 mol) and 1.5 mol/L hydrochloric acid (605 mL)were added to ethanol (2.5 L) and the mixture was heated to 90° C. withstirring. To this mixture was added(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine 4 times(30 g each time) every 30 min. The mixture was heated under reflux for 5hrs and the inner temperature was set to 50° C. 2N Aqueous sodiumhydroxide solution (450 mL) and 1N aqueous sodium hydroxide solutionwere added to adjust the pH thereof to 7-8 and the mixture was stirredfor a while. Ethyl acetate (1 L) and Celite (300 g) were added, andafter stirring for a while, the mixture was filtered through Celite. Theresidue was washed with THF-ethyl acetate (1:1, 1 L) and the filtratewas concentrated under reduced pressure. Water (1 L) was added to theconcentrate and the product was collected by filtration and dried underreduced pressure at 60° C. overnight to give the title compound (108.76g, 98%).

5: ¹H NMR (DMSO-d₆) δ ppm: 5.77 (s, 2H), 7.43 (t, J=9.3 Hz, 1H), 7.60(s, 1H), 7.80 (m, 1H), 7.94 (s, 1H), 8.18 (dd, J=6.9, 2.1 Hz, 1H), 8.39(s, 1H), 9.72 (s, 1H).

Synthetic Example 6 Synthesis of[4-(1,1-dimethyl-2-propynyl)-1-piperazinyl]acetonitrile (4c)

To a suspension (10 mL) of 1-(1,1-dimethyl-2-propynyl)piperazine (350mg, 2.3 mmol) and potassium carbonate (480 mg, 3.45 mmol) in methylethyl ketone (MEK) was added bromoacetonitrile (0.176 mL, 2.53 mmol),and the mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with MEK and filtered. The filtrate was concentratedto give the title compound (0.439 g, quantitative) as a white solid.

4c: ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.40 (s, 6H), 2.31 (s, 1H), 2.68 (brs, 8H), 3.52 (s, 2H).

Example 3

1) Triethylamine (15 mL) and DMF (3.5 mL) were added to compound 5 (1.0g, 2.72 mmol) and[4-(1,1-dimethyl-2-propynyl)-1-piperazinyl]acetonitrile (4c) (624 mg,3.26 mmol). This mixture was subjected 3 times to the step of degassingunder reduced pressure and displacement with nitrogen, andtriphenylphosphine (35 mg, 0.16 mmol) and palladium (II) acetate (18 mg,0.08 mmol) were added. The mixture was stirred at 80° C. for 4 hrs. Thereaction mixture was allowed to cool to room temperature and the solventwas evaporated under reduced pressure. Aqueous sodium hydrogen carbonatewas added to the residue and the mixture was extracted with ethylacetate. The organic layer was washed successively with water andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was subjected tosilica gel column chromatography (ethyl acetate-methanol) to give theobjective coupling compound 2c (1.07 g, 82%).

2c: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 2.56 (br s, 4H), 2.70(br s, 4H), 3.73 (s, 2H), 5.54 (s, 2H), 7.42 (t, J=8.9 Hz, 1H), 7.51 (s,1H), 7.64 (S, 1H), 7.81 (m, 1H), 8.20 (dd, J=6.9, 2.4 Hz, 1H), 8.39 (s,1H), 9.64 (s, 1H).2) A solution of compound 2c (500 mg, 1.04 mmol), acrylic acid (0.36 mL,5.2 mmol), triethylamine (0.22 mL, 1.56 mmol) and EDC (297 mg, 1.56mmol) in DMF (7 mL) was stirred overnight at room temperature. Thereaction mixture was evaporated under reduced pressure and poured intoaqueous sodium hydrogen carbonate (70 mL). The mixture was filtered andthe residue was washed with water and water-ethanol. The purified crudesubstance was subjected to silica gel column chromatography(chloroform-methanol) and the obtained solid was recrystallized fromwater-ethanol to give the objective compound 1c (338 mg, 61%).

1c: ¹H NMR (DMSO-d₆) δ ppm: 1.44 (s, 6H), 2.50 (br s, 4H), 2.67 (br s,4H), 3.71 (s, 2H), 5.84 (d, J=10.1 Hz, 1H), 6.32 (d, J=16.9 Hz, 1H),6.56 (dd, J=16.9, 10.1 Hz, 1H),7.46 (t, J=9.2 Hz, 1H), 7.84 (br s, 2H),8.18 (br d, J=6.8 Hz, 1H), 8.63 (s, 1H), 8.67 (s, 1H), 9.89 (s, 1H),9.99 (s, 1H).

Examples 4-25

In the same manner as in Example 3 and using7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine (5) and thecorresponding acetylene compound 4 as starting materials, amines 2 andcompounds 1 were produced as shown in the following (Scheme 5). Eachspectrum data are shown in Table 10.

TABLE 10 Ex. R³ Compound 1 (yield) Compound 2 (yield) Compound 4, R3—H 4

1d(40%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.43(s, 6H),2.82(t, J=6.8 Hz,4H),3.24(s, 6H), 3.33-3.50(m, 4H),5.85(dd, J=10.0, 1.9 Hz, 1H),6.33(dd,J=17.0, 1.9 Hz, 1H),6.56(dd, J=17.0,10.0 Hz, 1H),7.46(t, J=9.2 Hz,1H),7.83(br s, 2H),8.18(br d,J=7.0 Hz, 1H), 8.63(s, 1H),8.68(s, 1H),9.88(s, 1H),9.99(s, 1H). 2d(62%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.47(s,6H),2.86(t, J=6.8 Hz, 4H),3.26(s, 6H),3.43(t, J=6.8 Hz, 4H),5.56(s,2H),7.42(t, J=9.2 Hz, 1H),7.51(s, 1H), 7.64(s, 1H),7.83(m, 1H),8.21(dd,J=6.8, 2.4 Hz, 1H),8.39(s, 1H), 9.62(s, 1H). 4d·HCl(51%):1H NMR(300MHz,CDCl3) δ ppm:1.91(s, 6H), 2.68(s, 1H),3.47(s, 6H), 3.57-3.75(m, 4H),3.80-3.90(m, 2H), 4.00-4.15(m, 2H), 12.23(br s, 1H) 5

1e(36%): 1H NMR(270 MHz,DMSO-d6) δ ppm:1.26(m, 1H), 1.50-1.64(m, 7H),2.00(m, 2H),2.15(s, 3H), 2.35(br s, 4H),2.64(br s, 4H),5.83(dd, J=10.0,1.9 Hz, 1H),6.31(dd, J=17.0, 1.9 Hz, 1H),6.55(dd, J=17.0,10.0 Hz,1H),7.46(t, J=8.9 Hz, 1H),7.85(br s,2H),8.19(br d, J=6.8 Hz, 1H),8.64(s,1H), 8.65(s, 1H),9.88(s, 1H), 9.99(s, 1H). 2e(89%):1H NMR(270MHz,DMSO-d6) δ ppm:1.35(m, 1H), 1.50-1.75(m, 7H), 1.99(m, 2H),2.20(s,3H), 2.45(br s, 4H),2.67(br s, 4H), 5.50(s, 2H),7.43(t, J=8.9 Hz,1H),7.54(s, 1H), 7.66(s, 1H),7.79-7.85(m, 1H),8.21(dd, J=7.0, 2.7 Hz,1H),8.40(s, 1H), 9.65(s, 1H). 4e(83%):1H NMR(300 MHz,DMSO-d6) δppm:1.13-1.31(m, 1H), 1.32-1.52(m, 5H), 1.52-1.70(m, 2H), 1.70-1.87(m,2H), 2.13(s, 3H),3.20-2.41(m, 4H), 2.41-2.65(m, 4H), 3.18(s, 1H). 6

1f(30%): 1H NMR(270 MHz,DMSO-d6) δ ppm:1.42(s, 6H), 2.14(s, 6H),2.26(s,3H),2.31(t, J=7.2 Hz, 2H),2.56(t, J=7.2 Hz, 2H),5.84(dd, J=10.0, 1.9 Hz,1H),6.33(dd, J=16.7, 1.9 Hz, 1H),6.56(dd, J=16.7,10.0 Hz, 1H),7.46(t,J=9.2 Hz, 1H),7.84(br s,2H),8.18(br d, J=7.0 Hz, 1H),8.62(s, 1H),8.67(s, 1H),9.90(s, 1H), 10.00(s, 1H). 2f(70%): 1H NMR(270 MHz,DMSO-d6)δ ppm:1.46(s, 6H), 2.16(s, 6H),2.30(s, 3H),2.35(t, J=7.6 Hz, 2H),2.61(t,J=7.6 Hz, 2H),5.55(s, 2H),7.42(t, J=9.2 Hz, 1H),7.50(s, 1H), 7.63(s,1H),7.81(m, 1H),8.20(dd, J=6.8, 2.7 Hz, 1H),8.39(s, 1H), 9.63(s, 1H).4f(78%): 1H NMR(300 MHz,DMSO-d6) δ ppm:1.25(s, 6H), 2.10(s, 6H),2.15(s,3H), 2.20-2.30(m, 2H), 2.36-2.46(m, 2H), 3.09(s, 1H). 7

1g(44%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.11(t, J=7.0 Hz, 6H),2.11(s, 3H),2.31(br s, 4H),2.67(br s, 4H),3.51(q, J=7.0 Hz, 4H),3.67(s, 4H),5.85(dd,J=10.0, 1.9 Hz, 1H),6.32(dd, J=17.0, 1.9 Hz, 1H),6.54(dd, J=17.0,10.0Hz, 1H),7.44(t, J=8.9 Hz, 1H),7.81(br s, 2H),8.15(br d, J=6.8 Hz,1H),8.61(s, 1H), 8.73(s, 1H),9.74(s, 1H), 10.00(s, 1H). 2g(73%):1HNMR(DMSO-d6) δ ppm:1.15(t, J=7.0 Hz, 6H),2.16(s, 3H), 2.38(br s,4H),2.71(br s, 4H),3.53(q, J=7.0 Hz, 4H),3.67(s, 4H), 5.71(s,2H),7.43(t, J=9.2 Hz, 1H),7.50(s, 1H), 7.62(s, 1H),7.81(m, 1H),8.20(dd,J=7.0, 2.7 Hz, 1H),8.38(s, 1H), 9.65(s, 1H). 4g(83%):1H NMR(300MHz,DMSO-d6) δ ppm:1.09(t, J=6.9 Hz, 6H),2.14(S, 3H), 2.20-2.45(m, 4H),2.50-2.70(m, 4H), 3.20(s, 1H),3.45(q, J=6.9 Hz, 4H),3.55-3.60(m, 4H). 8

1h(50%):1H NMR(270 MHz,DMSO-d6) δ ppm:0.98(t, J=7.3 Hz, 3H),1.43(s,6H),2.28(q, J=7.3 Hz, 2H),2.38(br s, 4H), 2.64(br s, 4H),5.83(dd,J=10.3, 1.9 Hz, 1H),6.33(dd, J=17.0, 1.9 Hz, 1H),6.58(dd, J=17.0,10.3Hz, 1H),7.46(t, J=8.9 Hz, 1H),7.84(br s,2H),8.18(br d, J=6.5 Hz,1H),8.63(s, 1H), 8.69(s, 1H),9.87(s, 1H), 10.01(s, 1H). 2h(85%):1HNMR(270 MHz,DMSO-d6) δ ppm:1.00(t, J=7.0 Hz, 3H),1.47(s, 6H),2.33(q,J=7.0 Hz, 2H),2.44(br s, 4H),2.67(br s, 4H),5.53(s, 2H),7.42(t, J=9.2Hz, 1H),7.53(s, 1H), 7.65(s, 1H),7.83(m, 1H),8.21(dd, J=6.8, 2.4 Hz,1H),8.40(s, 1H), 9.63(s, 1H). 4h(94%):1H NMR(300 MHz,CDCl3) δppm:1.07(t, J=7.2 Hz, 3H),2.26(s, 1H),2.40(q, J=7.2 Hz, 2H),2.51(br s,4H),2.69(br s, 4H). 9

1i(53%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.42(s, 6H), 2.29(s, 3H),2.64(t,J=6.2 Hz, 2H),3.24(s, 3H),3.40(t, J=6.2 Hz, 2H),5.85(dd, J=10.0, 1.9 Hz,1H),6.33(dd, J=17.0, 1.9 Hz, 1H),6.56(dd, J=17.0,10.0 Hz, 1H),7.46(t,J=8.9 Hz, 1H),7.84(br s,2H),8.19(br d, J=7.0 Hz, 1H),8.63(s, 1H),8.67(s, 1H),9.89(s, 1H), 9.99(s, 1H). 2i(71%):1H NMR(270 MHz,DMSO-d6) δppm:1.46(s, 6H), 2.32(s, 3H),2.68(t, J=6.2 Hz, 2H),3.26(s, 3H),3.44(t,J=6.2 Hz, 2H),5.57(s, 2H),7.43(t, J=8.9 Hz, 1H),7.51(s, 1H), 7.64(s,1H),7.82(m, 1H),8.21(dd, J=6.8, 2.7 Hz, 1H),8.39(s, 1H), 9.65(s, 1H).4i·HCl(56%):1H NMR(300 MHz,DMSO-d6) δ ppm:1.66(s, 1H), 2.79(S,3H),3.00-3.20(m, 1H),3.31(s, 3H), 3.50-3.70(m, 1H), 3.70-3.95(m, 2H),4.00(s, 1H),11.11(br s, 1H). 10

1j(50%): 1H NMR(270 MHz,DMSO-d6) δ ppm:1.43(s, 6H), 1.74(m, 2H),2.22(s,3H), 2.50(m, 4H),2.83(m, 4H),5.85(dd, J=10.0, 1.9 Hz, 1H),6.33(dd,J=17.0, 1.9 Hz, 1H),6.56(dd, J=17.0,10.0 Hz, 1H),7.46(t, J=9.2 Hz,1H),7.82(br s, 2H),8.18(br d,J=6.8 Hz, 1H),8.63(s, 1H), 8.67(s,1H),9.88(s, 1H), 9.99(s, 1H). 2j(66%): 1H NMR(270 MHz,DMSO-d6) δppm:1.43(s, 6H), 1.77(m, 2H),2.24(s, 3H), 2.50(m, 4H),2.85(m, 4H),5.55(s, 2H),7.43(t, J=8.9 Hz, 1H),7.51(s, 1H), 7.62(s, 1H),7.82(m,1H),8.21(dd, J=7.0, 2.4 Hz, 1H),8.39(s, 1H), 9.65(s, 1H).4j·xHCl(71%:X=2

):1H NMR(300 MHz,DMSO-d6) δ ppm:1.69(s, 6H), 2.32(br s, 2H),2.79(s, 3H),3.50-4.00(m, 8H), 4.01(s, 1H). 11

1k(36%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.37(m, 2H), 1.42(s, 6H),1.72(m,2H), 2.23(m, 2H),2.94(m, 2H), 3.48(m, 1H),4.54(d, J=4.3 Hz, 1H),5.85(d,J=10.3 Hz, 1H),6.31(d, J=17.3 Hz, 1H),6.54(dd, J=17.3,10.3Hz,1H),7.44(t, J=9.2 Hz, 1H),7.82(br s, 2H),8.17(br d, J=6.8 Hz,1H),8.61(s, 1H), 8.65(s, 1H),9.87(s, 1H), 9.98(s, 1H). 2k(63%):1HNMR(270 MHz,DMSO-d6) δ ppm:1.39(m, 2H), 1.47(s, 6H),1.75(m, 2H), 2.30(m,2H),2.98(m, 2H), 3.48(m, 1H),4.55(m, 1H), 5.53(s, 2H),7.42(t, J=9.2 Hz,1H),7.51(s, 1H), 7.63(s, 1H),7.82(m, 1H),8.20(dd, J=6.8, 2.7 Hz,1H),8.39(s, 1H), 9.63(s, 1H). 4k(54%):1H NMR(300 MHz,CDCl3) δppm:1.41(s, 6H), 1.52-1.63(m, 3H), 1.90-2.02(m, 2H), 2.29(s, 1H),2.35(m,2H), 2.95(m, 2H),3.70(m, 1H). 12

1l(50%):1H NMR(300 MHz,DMSO-d6) δ ppm:1.52(s, 6H),2.37(t, J=6.0 Hz,4H),2.92(t, J=6.0 Hz, 4H),5.83(d, J=10.1 Hz, 1H),6.31(d, J=17.1 Hz,1H),6.51(dd, J=10.1,17.1 Hz, 1H),7.45(t, J=9.1 Hz, 1H),7.83(m, 1H),7.87(s, 1H),8.18(dd, J=2.3,6.8 Hz, 1H),8.63(s, 2H), 9.98(s, 1H),10.00(s,1H). 2l(98%):1H NMR(300 MHz,DMSO-d6) δ ppm:1.57(s, 6H),2.41(t, J=5.8 Hz,4H),2.95(t, J=5.8 Hz, 4H),5.55(br s, 2H),7.42(t, J=9.1 Hz, 1H),7.66(s,1H), 7.80(m, 1H),8.19(dd, J=2.6, 6.9 Hz, 1H),8.31(s, 1H), 8.31(s,1H),8.38(s, 1H), 9.64(s, 1H). 4l(56%):1H NMR(300 MHz,CDCl3) δppm:1.47(s, 6H), 2.32(s, 1H),2.48(t, J=6.1 Hz, 4H),2.93(t, J=6.1 Hz,4H). 13

1m(52%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.44(s, 6H), 2.71(br s,4H),2.86(s, 3H), 3.12(br s, 4H),5.85(dd, J=10.3, 1.9 Hz, 1H),6.31(dd,J=17.3, 1.9 Hz, 1H),6.54(dd, J=17.3,10.3 Hz, 1H),7.44(t, J=9.2 Hz,1H),7.82(br s, 2H),8.17(br d, J=6.8Hz, 1H),8.61(s, 1H), 8.65(s,1H),9.87(s, 1H), 9.98(s, 1H). 2m(51%):1H NMR(270 MHz,DMSO-d6) δppm:1.50(s, 6H), 2.76(br s, 4H),2.89(s, 3H), 3.16(br s, 4H),5.55(s,2H),7.42(t, J=9.2 Hz, 1H),7.51(s, 1H), 7.66(s, 1H),7.82(m, 1H),8.20(dd,J=6.8, 2.7 Hz, 1H),8.39(s, 1H), 9.64(s, 1H). 4m(85%):1H NMR(300MHz,CDCl3) δ ppm:1.43(s, 6H), 2.31(s, 1H),2.79(s, 3H), 2.80(br s,4H),3.29(br s, 4H). 14

1n(45%):1H NMR(270 MHz,DMSO-d6) δ ppm:0.89(t, J=7.2 Hz, 6H),1.60-1.80(m,4H),2.13(s, 3H), 2.32(br s, 4H),2.60(br s, 4H),5.82(d, J=10.0 Hz,1H),6.30(d, J=17.0 Hz, 1H),6.52(dd, J=17.0,10.0 Hz, 1H),7.44(t, J=9.2Hz, 1H),7.82(br s,2H),8.17(br d, J=6.8 Hz, 1H),8.62(s, 1H), 8.63(s,1H),9.88(s, 1H), 9.98(s, 1H). 2n(77%):1H NMR(270 MHz,DMSO-d6) δppm:0.92(t, J=7.3 Hz, 6H),1.65-1.97(m, 4H),2.15(s, 3H), 2.37(br s,4H),2.62(br s, 4H), 5.47(s, 2H),7.41(t, J=9.2 Hz, 1H),7.52(s, 1H),7.63(s, 1H),7.80(m, 1H),8.19(dd, J=6.9, 2.4 Hz, 1H),8.38(s, 1H), 9.63(s,1H). 4n(32%):1H NMR(300 MHz,CDCl3) δ ppm:0.83(t, J=7.3 Hz,6H),1.43-1.70(m, 4H),2.12(s, 3H), 2.17-2.37(m, 4H), 2.40-2.59(m,4H),3.13(d, J=1.7 Hz, 1H). 15

1o(44%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.42(br s, 8H), 1.86(m,2H),2.27(t, J=10.6 Hz, 2H),2.93(m, 2H), 3.11(m, 1H),3.20(s, 3H),5.84(dd,J=10.0, 1.9 Hz, 1H),6.32(dd, J=17.0, 1.9 Hz, 1H),6.55(dd, J=17.0,10.0Hz, 1H),7.44(t, J=9.2 Hz,1H),7.82(br s, 2H),8.17(br d, J=7.0 Hz,1H),8.61(s, 1H), 8.65(s, 1H),9.90(s, 1H), 9.98(s, 1H). 2o(62%):1HNMR(270 MHz,DMSO-d6) δ ppm:1.46(br s, 8H), 1.86(m, 2H),2.33(t, J=10.0Hz, 2H),2.92(m, 2H), 3.17(m, 1H),3.22(s, 3H), 5.53(s, 2H),7.41(t, J=9.2Hz, 1H),7.49(s, 1H), 7.62(s, 1H),7.80(m, 1H),8.19(dd, J=6.8, 2.7 Hz,1H),8.37(s, 1H), 9.62(s, 1H). 4o(51%):1H NMR(300 MHz,DMSO-d6) δppm:1.29(s, 6H), 1.25-1.55(m, 2H), 1.75-1.90(m, 2H), 2.20(m, 2H),2.81(m,2H), 3.12(m, 1H),3.21(m, 3H), 3.33(s, 1H). 16

1p(38%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.44(s, 6H), 1.97(s, 3H),2.55(brs, 2H), 2.61(br s, 2H),3.42(br s, 4H),5.82(dd, J=10.0, 1.9 Hz,1H),6.30(dd, J=17.0, 1.9 Hz, 1H),6.51(dd, J=17.0,10.0 Hz, 1H),7.44(t,J=9.2 Hz,1H),7.83(br s, 2H),8.16(br d, J=6.8 Hz, 1H),8.61(s, 1H),8.63(s, 1H),9.91(s, 1H), 9.98(s, 1H). 2p(66%):1H NMR(270 MHz,DMSO-d6) δppm:1.49(s, 6H), 1.98(s, 3H),2.58(br s, 2H), 2.64(br s, 2H),3.46(br s,4H), 5.53(s, 2H),7.41(t, J=9.2 Hz, 1H),7.49(s, 1H), 7.63(s, 1H),7.80(m,1H),8.19(dd, J=6.8, 2.7 Hz, 1H),8.37(s, 1H), 9.63(s, 1H). 4p(49%):1HNMR(300 MHz,DMSO-d6) δ ppm:1.32(s, 6H), 1.99(s, 3H),2.41-2.59(m,4H),3.18(s, 1H),3.43(br t, J=4.4 Hz, 4H). 17

1q(64%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.02(t, J=7.2 Hz, 3H),1.43(s, 6H),2.50(br s, 2H),2.69(q, J=7.2 Hz, 2H),2.92(t, J=7.2 Hz, 2H),3.59(s,3H),5.84(d, J=10.0 Hz, 1H),6.32(d, J=17.0 Hz, 1H),6.55(dd, J=17.0,10.0Hz,1H),7.46(t, J=9.2 Hz, 1H),7.83(br s, 2H),8.19(br d, J=6.8 Hz,1H),8.63(s, 1H), 8.67(s, 1H),9.90(s, 1H), 9.99(s, 1H). 2q(43%):1HNMR(270 MHz,DMSO-d6) δ ppm:1.05(t, J=7.0 Hz, 3H),1.46(s, 6H), 2.49(br s,2H),2.71(q, J=7.0 Hz, 2H),2.94(t, J=7.3 Hz, 2H),3.58(s, 3H), 5.53(s,2H),7.41(t, J=9.2 Hz, 1H),7.48(s, 1H), 7.61(s, 1H),7.80(m, 1H),8.19(dd,J=6.8, 2.4 Hz, 1H),8.37(s, 1H), 9.62(s, 1H). 4q(50%):1H NMR(300MHz,CDCl3) δ ppm:1.08(t, J=7.2 Hz, 3H),1.39(s, 6H), 2.23(s, 1H),2.53(t,J=7.7 Hz, 2H),2.67(q, J=7.2 Hz, 2H),2.94(t, J=7.7 Hz, 2H),3.67(s, 3H).18

1r(38%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.42(s, 6H),2.43(brt, J=6.0 Hz,6H),2.62(br s, 4H), 3.22(s, 3H),3.41(t, J=6.0 Hz, 2H),5.84(d, J=10.3 Hz,1H),6.33(d, J=16.7 Hz, 1H),6.57(dd, J=16.7,10.3 Hz, 1H),7.46(t, J=9.2Hz, 1H),7.84(br s, 2H),8.19(br d,J=6.8 Hz, 1H),8.63(s, 1H), 8.68(s,1H),9.87(s, 1H), 10.00(s, 1H). 2r(53%):1H NMR(270 MHz,DMSO-d6) δppm:1.45(s, 6H),2.43(t, J=6.0 Hz, 2H),2.49(br s, 4H), 2.63(br s,4H),3.21(s, 3H),3.41(t, J=6.0 Hz, 2H),5.53(s, 2H),7.41(t, J=9.2 Hz,1H),7.50(s, 1H), 7.62(s, 1H),7.80(m, 1H),8.19(dd, J=7.0, 2.7 Hz,1H),8.37(s, 1H), 9.63(s, 1H). 4r: 1H NMR(300 MHz,CDCl3) δ ppm:1.40(s,6H), 2.27(s, 1H),2.59(m, 6H), 2.72(br s, 4H),3.35(s, 3H), 3.53(m, 2H).19

1s(48%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.43(s, 6H), 2.46-2.57(m, 6H),2.62-2.68(m, 6H),5.86(dd, J=10.0, 1.9 Hz, 1H),6.33(dd, J=16.7, 1.9 Hz,1H),6.57(dd, J=16.7,10.0 Hz, 1H),7.46(t, J=9.2 Hz, 1H),7.84(br s,2H),8.19(br d, J=7.0 Hz, 1H), 8.63(s, 1H),8.67(s, 1H),9.88(s, 1H),10.00(s, 1H). 2s(72%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.46(s, 6H),2.40-2.58(m, 6H), 2.60-2.75(m, 6H), 5.53(s, 2H),7.41(t, J=9.2 Hz,1H),7.49(s, 1H), 7.62(s, 1H),7.80(m, 1H),8.19(dd, J=7.0, 2.7 Hz,1H),8.37(s, 1H), 9.63(s, 1H). 4s: 1H NMR(300 MHz,CDCl3) δ ppm:1.40(s,6H), 2.30(s, 1H),2.52(t, 2H), 2.45-2.65(m, 4H), 2.65-2.85(m, 6H). 20

1t(46%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.44(s, 6H), 1.68(br s,4H),2.68(br s, 4H),5.85(dd, J=10.0, 1.9 Hz, 1H),6.32(dd, J=17.0, 1.9 Hz,1H),6.54(dd, J=17.0,10.0 Hz, 1H),7.46(t, J=9.2 Hz, 1H),7.84(br s,2H),8.19(br d, J=6.8 Hz,1H),8.63(s, 1H), 8.65(s, 1H),9.91(s, 1H),9.99(s, 1H). 2t(75%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.47(s, 6H), 1.72(brs, 4H),2.71(br s, 4H), 5.51(s, 2H),7.41(t, J=9.2 Hz, 1H),7.49(s, 1H),7.62(s, 1H),7.81(m, 1H),8.19(dd, J=7.0, 2.7 Hz, 1H),8.37(s, 1H), 9.62(s,1H). 4t(52%):1H NMR(300 MHz,CDCl3) δ ppm:1.42(s, 6H), 1.80(m,4H),2.24(s, 1H), 2.72(m, 4H). 21

1u(33%):¹H NMR(270 MHz,DMSO-d6) δ ppm:1.45(s, 6H), 2.30(s, 3H),2.65(t,J=5.8 Hz, 2H),2.74(t, J=5.8 Hz, 2H),5.85(d, J=10.0 Hz, 1H),6.33(d,J=17.0 Hz, 1H),6.56(dd, J=17.0,10.0 Hz, 1H),7.46(t, J=9.2 Hz,1H),7.87(br s,2H),8.19(br d, J=6.8 Hz, 1H),8.63(s, 1H), 8.66(s,1H),9.93(s, 1H), 10.00(s, 1H). 2u(quant):1H NMR(270 MHz,DMSO-d6) δppm:1.49(s, 6H), 2.34(s, 3H),2.65-2.80(m, 4H),5.56(s, 2H),7.43(t, J=9.2Hz, 1H),7.50(s, 1H), 7.66(s, 1H),7.81(m, 1H),8.20(dd, J=7.0, 2.4 Hz,1H),8.39(s, 1H), 9.64(s, 1H). 4u·HCl(81%):1H NMR(300 MHz,DMSO) δppm:1.64(s, 6H), 2.75(s, 3H),3.17(brt, J=6.8 Hz, 2H),3.30-3.70(m,2H),3.98(s, 1H);4u: 1H NMR(300 MHz,CDCl3) δ ppm:1.38(s, 6H), 2.27(s,1H),2.30(s, 3H),2.48(t, J=6.9 Hz, 2H),2.78(t, J=6.9 Hz, 2H). 22

1v(72%):¹H NMR(300 MHz,DMSO-d6) δ ppm:2.20-2.50(m, 4H), 2.50-2.64(m,2H), 2.64-2.75(m, 2H), 3.40-3.60(m, 4H),5.83(dd, J=1.3, 10.2 Hz,1H),6.32(dd, J=1.3, 10.2 Hz, 1H),6.62(dd, J=10.2,17.1 Hz,1H),7.42(t,J=9.1 Hz, 1H),7.70-7.82(m, 1H),7.80(s, 1H),8.11(dd, J=2.3,6.8 Hz, 1H),8.56(s, 1H), 8.74(s, 1H),9.89(s, 1H), 9.98(s, 1H).2v(59%):1H NMR(300 MHz,DMSO-d6) δ ppm:2.15-2.50(m, 4H), 2.50-2.65(m,2H),2.65-2.80(m, 2H),3.50-3.75(m, 4H),5.91(s, 2H),7.42(t, J=8.9 Hz,1H),7.44(s, 1H), 7.59(s, 1H),7.80(m, 1H),8.18(dd, J=2.4,6.7 Hz,1H),8.36(s, 1H), 9.61(s, 1H). 4v·HCl(74%):1H NMR(300 MHz,DMSO-d) δppm:2.78(dt, J=2.4, 7.7 Hz, 2H),3.00-3.20(m, 2H),3.10(t, J=2.4 Hz,1H),3.20-3.35(m, 2H),3.35-3.50(m, 2H),3.70-3.88(m, 2H),3.90-4.00(m,2H),11.47(br s, 1H). 23

1x(59%):1H NMR(300 MHz,DMSO-d6) δ ppm:2.45-2.65(m, 4H),3.50-3.70(m,6H),5.84(dd, J=1.4, 10.3 Hz, 1H),6.33(dd, J=1.4,17.0 Hz, 1H),6.60(dd,J=10.3,17.0 Hz, 1H),7.46(t, J=9.1 Hz, 1H),7.82(m, 1H),7.89(s,1H),8.18(dd, J=2.3, 6.7 Hz, 1H),8.62(s, 1H), 8.72(s, 1H),10.01(s, 1H),10.02(s, 1H). 2x(59%):1H NMR(300 MHz,DMSO-d6) δ ppm:2.50-2.70(m,4H),3.45-3.75(m, 6H),5.68(br s, 2H),7.43(t, J=9.1Hz, 1H),7.49(s, 1H),7.67(s, 1H),7.76-7.86(m, 1H),8.20(dd, J=2.2, 6.7 Hz, 1H),8.38(s, 1H),9.64(s, 1H). 4x(98%):1H NMR(300 MHz,CDCl₃) δ ppm:2.28(t, J=2.2 Hz,1H),2.57(t, J=4.6 Hz, 4H),3.30(d, J=2.2 Hz, 2H),3.75(t, J=4.6 Hz, 4H).24

1y(39%):1H NMR(300 MHz,DMSO-d6) δ ppm:2.16(s, 3H), 2.34(br s,4H),2.56(br s, 4H), 3.60(s, 2H),5.84(d, J=10.1 Hz, 1H),6.33(d, J=16.9Hz, 1H),6.61(dd, J=16.9 Hz,10.1 Hz, 1H),7.46(t, J=9.0 Hz,1H),7.76-7.90(m, 1H),7.87(s, 1H),8.17(m, 1H),8.62,(s, 1H), 8.73(s,1H),9.98(s, 1H), 10.01(s, 1H). 2y(93%):1H NMR(300 MHz,DMSO-d6) δppm:2.17(s, 3H), 2.10-2.40(m, 4H), 2.40-2.75(m, 4H), 3.65(s, 2H),5.68(brs, 2H),7.42(t, J=9.1Hz),7.48(s, 1H), 7.66(s, 1H),7.73-7.85(m,1H),8.18(dd, J=1.9, 6.6 Hz, 1H),8.37(s, 1H), 9.64(s, 1H). 4y(63%):1HNMR(300 MHz,CDCl₃) δ ppm:2.25(t, J=2.3 Hz, 1H),2.30(s, 3H), 2.30-2.85(m,8H),3.30(d, J=2.3 Hz, 2H). 25

1z(58%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.38(s, 9H), 1.43(s, 6H),2.49(brs, 4H), 2.56(br s, 4H),5.82(dd, J=10.0, 1.9 Hz, 1H),6.31(dd, J=16.7, 1.9Hz, 1H),6.52(dd, J=16.7,10.0 Hz, 1H),7.44(t, J=9.2 Hz, 1H),7.83(br s,2H),8.17(br d,J=7.0 Hz, 1H),8.61(s, 1H), 8.63(s, 1H),9.92(s, 1H),9.98(s, 1H). 2z(79%):1H NMR(270 MHz,DMSO-d6) δ ppm:1.39(s, 9H), 1.49(s,6H),2.51(br s, 4H), 2.60(br s, 4H),5.53(s, 2H),7.42(t, J=9.2 Hz,1H),7.50(s, 1H), 7.64(s, 1H),7.81(m, 1H),8.20(dd, J=6.8, 2.4 Hz,1H),8.39(s, 1H), 9.63(s, 1H). 4z(49%):1H NMR(300 MHz,CDCl₃) δppm:1.39(s, 6H), 1.46(s, 9H),2.29(s, 1H),2.58(t, J=5.1 Hz, 4H),3.45(t,J=5.1 Hz, 4H).

Synthetic Examples 7-12 Synthesis of acetylene 4

In the above-mentioned Examples 3-25, acetylene compound 4 used as thestarting material was synthesized according to the method of SyntheticExample 1, except when shown in the following Synthetic Example. In somecases, the compound was converted to the corresponding hydrochloride (4Nhydrochloric acid-ethyl acetate) and used. The yield and ¹H NMR spectrumdata are shown in the Table.

Synthetic Example 7

4g: A solution (360 mL, 180 mmol) of ethynyl magnesium chloride in 0.5 MTHF was stirred under ice-cooling and 1,3-diethoxyacetone (21.93 g, 150mmol) was added dropwise. The mixture was stirred under ice-cooling for30 min and acetic anhydride (18.4 mL, 195 mmol) was added dropwise. Themixture was stirred at room temperature for 1 hr. After the completionof the reaction, aqueous ammonium chloride solution was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium hydrogen carbonate and saturated brine,dried over anhydrous magnesium sulfate and concentrated to give aceticacid 1,1-bis-ethoxymethyl-2-propynyl ester (31.36 g, 97%).

Acetic acid 1,1-bis(ethoxymethyl)-2-propynyl ester (15.00 g, 70 mmol),1-methylpiperazine (8.41 g, 84 mmol), copper chloride (I) (350 mg) andtriethylamine (9.7 mL, 70 mmol) were dissolved in THF (150 mL) and themixture was heated under reflux for 2 hrs. After the completion of thereaction, ^(t)BuOMe was added to the reaction mixture and the mixturewas extracted with 3N hydrochloric acid. The extract was neutralizedwith 6N aqueous sodium hydroxide solution and extracted with ethylacetate. The organic layer was washed with 7% aqueous ammonium chloridesolution and water, dried over anhydrous magnesium sulfate andconcentrated to give the title compound 4 g (15.30 g, 86%).

Synthetic Example 8

4o: 1-(1,1-Dimethyl-2-propynyl)piperidin-4-ol 4k [synthesized accordingto the method of Synthetic Example 1 using 4-hydroxypiperidine as astarting material; yield 54%] (6.0 g, 36.0 mmol) was dissolved in THF(100 mL) and NaH (1.73 g) and methyl iodide (7.7 g) were added. Themixture was stirred for one day at room temperature. The reactionmixture was concentrated and water was added, and the mixture wasextracted with dichloromethane. The organic layer was dried overmagnesium sulfate. The organic layer was concentrated and the residuewas dissolved in ethyl acetate. 4N Hydrochloric acid-ethyl acetate (9mL) was added dropwise under ice-cooling, and the produced precipitatewas collected by filtration and dried to give 4o.HCl (4.0 g, 51%).

Synthetic Example 9

4m: A solution (60 mL) of 4-(1,1-dimethyl-2-propynyl)piperazine[synthesized according to the method of Synthetic Example 1 using anexcess of piperazine (2.5 equivalent amount) as a starting material;yield 42%] (6.0 g, 40.0 mmol) and pyridine (3.50 mL) in dichloromethanewas stirred under ice-cooling and methanesulfonyl chloride (5.6 g) wasadded. The mixture was gradually warmed to room temperature and waterwas added. The mixture was extracted with dichloromethane. The extractwas washed with aqueous sulfuric acid copper solution, water andsaturated brine and dried over magnesium sulfate. The organic layer wasconcentrated to give compound 4 m (7.80 g, 85%) as a pale-yellow solid.

Synthetic Example 10

4r: 1-(1,1-Dimethyl-2-propynyl)piperazine (5.0 g, 33 mmol),2-chloroethyl methyl ether (4.7 g, 50 mmol), sodium iodide (35.0 g, 233mmol) and potassium carbonate (9.2 g, 66 mmol) were suspended in methylethyl ketone (150 mL) and the reaction mixture was heated under refluxfor three days. The solvent was evaporated under reduced pressure andethyl acetate was added to the residue. The mixture was extracted with3N hydrochloric acid. The extract was neutralized with 6N aqueous sodiumhydroxide solution and extracted with dichloromethane. The organic layerwas washed with water and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue wasdissolved in ethyl acetate. 4N Hydrochloric acid-ethyl acetate (17.0 mL)was added, and the precipitated crystals were collected by filtrationand dried in vacuo to give compound 4r (7.44 g, 79%) as pale-yellowcrystals.

Synthetic Example 11

4s: 1-(1,1-Dimethyl-2-propynyl)piperazine (5.0 g, 33 mmol) andacrylonitrile (2.6 g, 49 mmol) were dissolved in methanol (50 mL) andthe mixture was stirred at room temperature for 3 hrs and at 55° C. for4 hrs. The reaction mixture was concentrated and dried in vacuo to givecompound 4s (6.51 g, 96%) as yellowish white crystals.

Synthetic Example 12

4v: A suspension (40 mL) of toluene-4-sulfonic acid 3-butynyl ester (4.0g, 17.8 mmol), morpholine (2.94 mL, 26.7 mmol) and potassium carbonate(2.96 g, 21.4 mmol) in acetonitrile was refluxed for 2.5 hrs. Afterallowing to cool, the mixture was filtered and the residue was washedwith ^(t)BuOMe (20 mL). The filtrate was concentrated and ^(t)BuOMe (40mL) was added. The product was extracted with 3N hydrochloric acid (30mL×1, 10 mL×1). 6N Aqueous sodium hydroxide solution was added to theextract until it showed basicity. The mixture was extracted withdichloromethane (40 mL×1, 20 mL×1). The organic layer was dried andconcentrated to give compound 4v (2.44 g, 98%) as an oil. This oil 4v(3.94 g, 28.2 mmol) was dissolved in diethyl ether (20 mL) and 4Nhydrochloric acid-ethyl acetate (7.8 mL, 31.2 mmol) was added dropwisewith stirring on an ice bath. After stirring at room temperature for 30min, the precipitate was collected by filtration. The residue was washedwith diethyl ether and dried under reduced pressure to give compound4v.HCl (3.78 g, 76%) as a white solid.

Example 26

1) To a solution (30 mL) of triethylamine (5.5 mL, 40 mmol) in ethanolwere added dimethylamine hydrochloride (3.26 g, 40 mmol), titantetraisopropoxide (11.8 mL, 40 mmol) and1-(1,1-dimethyl-2-propynyl)piperidin-4-one (41) (3.3 g, 20 mmol) at roomtemperature. After stirring for 7 hrs, NaBH₄ (1.13 g, 30 mmol) was addedand the mixture was stirred overnight at room temperature. The reactionmixture was poured into 5% aqueous ammonia (80 mL) and dichloromethane(100 mL) was added. The mixture was filtered through Celite and thefiltration residue was washed with dichloromethane (30 mL×3). Theorganic layer was partitioned, dried and filtered through silica gelcolumn (20 g). The filtrate was concentrated, and the obtained solid wassubjected to sublimation (oil bath temperature about 100° C./0.1 mmHg)under reduced pressure to give[1-(1,1-dimethyl-2-propynyl)-4-piperidinyl]dimethylamine (4aa) ascolorless crystals.2) A solution of7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine (5) (557 mg,1.52 mmol), compound 4aa (383 mg, 1.97 mmol) and triethylamine (12 mL)in DMF (2.4 mL) was subjected 3 times to the step of degassing underreduced pressure and displacement with nitrogen. Triphenylphosphine (24mg, 0.09 mmol) and palladium (II) acetate (10 mg, 0.05 mmol) were added.The mixture was stirred at 80° C. for 3 hrs and allowed to cool to roomtemperature. The solvent was evaporated under reduced pressure andaqueous sodium hydrogen carbonate was added to the residue. The mixturewas extracted with ethyl acetate, and the organic layer was washedsuccessively with water (×3) and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give an amino compound 2aa.3) A solution of the amino compound 2aa (690 mg, 1.43 mmol), acrylicacid (0.49 mL, 7.2 mmol), triethylamine (0.30 mL, 2.15 mmol) and EDC(410 mg, 2.15 mmol) in DMF (8 mL).was stirred overnight at roomtemperature. The reaction mixture was evaporated under reduced pressureand the residue was extracted with ethyl acetate. The organic layer waswashed successively with water (×3) and saturated brine and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The purified crude substance was subjected to silica gelcolumn chromatography (chloroform-methanol-triethylamine) and theobtained purified crude substance was recrystallized from water-ethanolto give the objective compound 1aa (127 mg, 16%).

1aa: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.32 (br d, 2H), 1.44 (s, 6H),1.76 (br d, J=11.2 Hz, 2H), 1.99 (m, 1H), 2.15 (br s, 8H), 3.10 (br d,J=11.3 Hz, 2H), 5.84 (d, J=10.1 Hz, 1H), 6.33 (d, J=17.0 Hz, 1H), 6.56(dd, J=17.0, 10.1 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.84 (br s, 2H), 8.19(br d, J=7.2 Hz, 1H), 8.63 (s, 1H), 8.66 (s, 1H), 9.91 (s, 1H), 9.99 (s,1H).

Example 27

1) A solution (9 mL) of(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine (3.0 g,7.55 mmol) obtained by a treatment, with triethylamine inwater-methanol, of(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride produced according to the method described in SyntheticExample 4, acetylene 4ab (1.76 g, 9.06 mmol) synthesized according tothe method of Synthetic Example 1 and triethylamine (60 mL) in DMFsolution was subjected 3 times to the step of degassing under reducedpressure and displacement with nitrogen. Triphenylphosphine (118 mg,0.46 mmol) and palladium (II) acetate (51 mg, 0.23 mmol) were added. Themixture was stirred at 80° C. for 3 hrs and allowed to cool to roomtemperature. The solvent was evaporated under reduced pressure andaqueous sodium hydrogen carbonate was added to the residue. The mixturewas extracted with ethyl acetate, and the organic layer was washedsuccessively with water (×3) and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give a nitro compound 3ab.

3ab: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 1.66 (m, 4H), 1.95(m, 2H), 2.14 (s, 3H), 2.33 (s, 3H), 2.79 (br d, J=11.6 Hz, 2H), 2.97(m, 1H), 7.48 (t, J=9.2 Hz, 1H), 7.80 (m, 1H), 7.88 (s, 1H), 8.16 (br d,J=7.0 Hz, 1H), 8.73 (s, 1H), 9.45 (s, 1H), 10.45-10.55 (br s, 1H).

4ab [synthesized according to the method of Synthetic Example 1; yield69%]: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.31 (s, 6H), 1.45-1.72 (m, 4H),1.77-1.93 (m, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.70-2.95 (m, 3H), 3.10(s, 1H).2) A mixture of the nitro compound 3ab, 1N hydrochloric acid (22.5 mL,22.5 mmol) and iron powder (2.09 g, 37.5 mmol) in ethanol (70 mL) wasrefluxed for 1.5 hrs. The reaction mixture was allowed to become 50° C.and 1N aqueous sodium hydroxide solution (22.5 mL, 22.5 mmol) was added.The mixture was stirred at 50° C. for 30 min. The reaction mixture wasallowed to cool to room temperature and filtered through Celite. Theresidue was washed with ethyl acetate and the filtrate was concentrated.Aqueous sodium hydrogen carbonate was added to the residue and themixture was extracted with ethyl acetate. The organic layer was washedsuccessively with water (×3) and saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was suspended in acetonitrile and the mixture wasstirred with heating under reflux. The mixture was allowed to reach roomtemperature and said residue was collected by filtration to give theobjective amino compound 2ab (2.78 g, 76%).

2ab: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.50 (s, 6H), 1.66 (m, 4H), 1.92(m, 2H), 2.13 (s, 3H), 2.33 (s, 3H), 2.79 (br d, J=10.8 Hz, 2H), 2.99(m, 1H), 5.53 (s, 2H), 7.42 (t, J=9.2 Hz, 1H), 7.50 (s, 1H), 7.57 (s,1H), 7.80 (m, 1H), 8.21 (dd, J=7.0, 2.4 Hz, 1H), 8.39 (s, 1H), 9.63 (s,1H).3) In the same manner as in Example 26-3), the amino compound 2ab wasconverted to the objective compound 1ab (yield 33%).

1ab: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 1.63 (m, 4H), 1.86(m, 2H), 2.10 (s, 3H), 2.30 (s, 3H), 2.74 (br d, J=10.8 Hz, 2H), 2.92(m, 1H), 5.85 (d, J=10.0 Hz, 1H), 6.33 (d, J=17.0 Hz, 1H), 6.56 (dd,J=17.0, 10.0 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.78 (s, 1H), 7.81 (m,1H), 8.18 (br d, J=6.6 Hz, 1H), 8.62 (s, 1H), 8.66 (s, 1H), 9.88 (s,1H), 9.99 (s, 1H).

Example 28

Using 4ac (yield 80%) synthesized in the same manner as in SyntheticExample 12 from 1-methylpiperazine and toluene-4-sulfonic acid 3-butynylester, and(7-bromo-6-nitro-4-quinazolinyl)-(3-chloro-4-fluorophenyl)amine asstarting materials, the converted compounds 3ac, 2ac and 1ac wereobtained in the same manner as in the above-mentioned Example 27.

4ac: ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.97 (t, J=2.6 Hz, 1H), 2.28 (s,3H), 2.38 (dt, J=2.6, 7.7 Hz, 2H), 2.46 (br s, 4H), 2.53 (br s, 4H),2.61 (t, J=7.7 Hz, 2H).

3ac: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.13 (s, 3H), 2.33 (br s, 4H),2.47 (br s, 4H), 2.59-2.73 (m, 4H), 7.48 (t, J=9.2 Hz, 1H), 7.79 (m,1H), 7.90 (s, 1H), 8.14 (dd, J=6.8,2.4 Hz, 1H), 8.72 (s, 1H), 9.38 (s,1H), 10.42 (br s, 1H).

2ac: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.16 (s, 3H), 2.36 (br s, 4H),2.47 (br s, 4H), 2.60 (t, J=6.5 Hz, 2H), 2.72 (t, J=6.5 Hz, 2H), 5.86(s, 2H), 7.42 (t, J=9.2 Hz, 1H), 7.46 (s, 1H), 7.58 (s, 1H), 7.81 (m,1H), 8.20 (dd, J=6.8, 2.7 Hz, 1H), 8.37 (s, 1H), 9.60 (s, 1H).

1ac: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.15 (s, 3H), 2.32 (br s, 4H),2.46 (br s, 4H), 2.60-2.69 (m, 4H), 5.86 (d, J=10.0 Hz, 1H), 6.35 (d,J=17.0 Hz, 1H), 6.65 (dd, J=17.0, 10.0 Hz, 1H), 7.45 (t, J=9.2 Hz, 1H),7.81 (br s, 2H), 8.16 (br d, J=7.0 Hz, 1H), 8.60 (s, 1H), 8.78 (s, 1H),9.86 (s, 1H), 10.00 (s, 1H).

Example 29

A mixture of compound 2a (2.40 g, 5.3 mmol) and 10% palladium carbon(170 mg) in THF (15 mL)-ethanol (15 mL) was stirred under a hydrogenatmosphere at room temperature for 12 hrs. The reaction mixture wasfiltered through Celite and the filtrate was concentrated. The residuewas subjected to silica gel chromatography (chloroform-methanol) to givean amino compound [m/z=455 (M+1)] (1.69 g, 70%). A solution (2 mL) ofthis amino compound (330 mg, 0.73 mmol), EDC (278 mg, 1.45 mmol),acrylic acid (99 μL) and triethylamine (200 μL) in DMF was stirredovernight at room temperature. Aqueous sodium hydrogen carbonate (40 mL)was added to the reaction mixture and the mixture was extracted withethyl acetate (40 mL×1, 20 mL×1). The extract was dried andconcentrated. The obtained crude purified substance was subjected tosilica gel column (chloroform-methanol-triethylamine), andsuspension-washed with acetonitrile to give the objective compound 1ad(200 mg, 54%).

1ad: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 0.96 (s, 6H), 1.99 (s, 3H),2.00-2.25 (m, 4H), 2.25-2.60 (m, 4H), 5.73 (d, J=12.9 Hz, 1H), 5.81 (d,J=10.4 Hz, 1H), 6.30 (d, J=16.9 Hz, 1H), 6.48 (d, J=12.9 Hz, 1H), 6.59(dd, J=10.4, 16.9 Hz, 1H), 7.45 (t, J=9.1 Hz, 1H), 7.80-7.92 (m, 1H),7.90 (s, 1H), 8.20 (dd, J=2.2, 6.7 Hz, 1H), 8.61 (s, 1H), 9.80 (s, 1H),9.92 (s, 1H).

Example 30

A mixture of compound 4ac (333 mg, 2.18 mmol), tributyltin hydride (764mg, 2.62 mmol) and 2,2′-azobisisobutyronitrile (4 mg, 0.02 mmol) wasstirred at 80° C. for 2 hrs. To this solution were added compound 5 (670mg, 1.80 mmol), palladium (II) acetate (10 mg), triphenylphosphine (24mg), DMF (1.3 mL) and triethylamine (7 mL), and the mixture was stirredat 80° C. for 4 hrs. To the reaction mixture was added Pd₂(dba)₃(dba=dibenzylidenacetone) (15 mg) and the mixture was stirred underrefluxing for 4 hrs. After allowing to stand to cool, aqueous potassiumfluoride solution (50 mL) was added and the mixture was stirred at roomtemperature for a while. The product was extracted with ethyl acetate(50 mL×1, 20 mL×2). The organic layer was dried and concentrated. Theresidue was subjected to silica gel column chromatography(chloroform-methanol-triethylamine) to give an oil (1.02 g) containingthe objective product. Using this oil (500 mg), EDC (345 mg, 1.8 mmol),acrylic acid (0.123 mL, 1.8 mmol), triethylamine (0.25 mL, 1.8 mmol) andDMF (4.0 mL) and in the same manner as in Example 1, the reaction wasconducted. The purified crude substance was subjected to columnchromatography (chloroform-methanol-triethylamine) and a small amount ofacetonitrile was added to the obtained oil (180 mg) to allowcrystallization. Acetonitrile (4 mL) was further added, and the mixturewas stirred under reflux and cooled to room temperature. The precipitatewas collected by filtration to give the objective compound 1ae (95 mg,theological yield 21%).

1ae: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.14 (s, 3H), 2.10-2.50 (m, 12H),5.82 (dd, J=1.5, 10.2 Hz, 1H), 6.29 (dd, J=1.5, 17.1 Hz, 1H), 6.52 (dt,J=6.0, 15.8 Hz, 1H), 6.58 (dd, J=10.2, 17.1 Hz, 1H), 6.67 (d, J=15.8 Hz,1H), 7.42 (t, J=9.1 Hz, 1H), 7.80 (m, 1H), 7.90 (s, 1H), 8.15 (dd,J=2.6, 6.8 Hz, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 9.88 (s, 1H), 10.03 (s,1H).

Example 31 1a.ditosylate (1a.2TsOH)

The compound 1a (10.00 g) was added to ethanol-ethyl acetate solution(1:7, 140 mL) and stirred. This was filtered [washed with ethanol-ethylacetate(1:7, 10 mL)] and a solution obtained by dissolvingp-toluenesulfonic acid (TsOH). monohydrate (7.37 g) in ethanol-ethylacetate solution (1:7, 20 mL) and filtering [washed with ethanol-ethylacetate (1:7, 10 mL)] was added to the obtained solution at roomtemperature. After stirring at room temperature 3 hrs, the resultingsolid was collected by filtration and dried under reduced pressure at70° C. for 5 hrs to give the title compound as pale-yellow crystals(15.96 g).

1a.2TsOH: ¹H NMR (DMSO-d₆) δ ppm: 1.49 (s, 6H), 2.27 (s, 6H), 2.59 (m,2H), 2.81 (s, 3H), 3.06 (m, 2H), 3.28 (m, 2H), 3.48 (m, 2H), 5.91 (d,J=10.2 Hz, 1H), 6.38 (d, J=16.9 Hz, 1H), 6.62 (dd, J=10.2 Hz, 16.9 Hz,1H), 7.10 (d, J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.57 (t, J=9.0 Hz,1H), 7.72 (m, 1H), 7.93 (s, 1H), 8.05 (dd, J=2.5 Hz, 6.8 Hz, 1H), 8.88(s, 1H), 8.94 (s, 1H), 9.39 (br s, 1H), 10.10 (s, 1H), 11.32 (br s, 1H).

Example 32 1a.trihydrochloride (1a.3HCl)

The compound 1a (1.549 g) was added to THF (40 mL), and the mixture wasstirred and filtered [washed with THF (6.5 mL)]. The obtained solutionwas ice-cooled, and 4N hydrochloric acid-ethyl acetate solution (2.37mL) was added dropwise. The mixture was stirred under ice-cooling for 5hrs, and the resulting product was collected by filtration and driedunder reduced pressure to give the title compound as a yellow solid(1.89 g).

1a.3HCl: ¹H NMR (DMSO-d₆) δ ppm : 1.75 (s, 6H), 2.86 (s, 3H), 3.25-3.90(m, 8H), 5.90 (dd, J=1.9, 10.3 Hz, 1H), 6.39 (dd, J=1.9, 17.0 Hz, 1H),6.86 (dd, J=10.3, 17.0 Hz, 1H), 7.58 (t, J=9.2 Hz, 1H), 7.74 (m, 1H),8.04 (dd, J=2.7, 6.8 Hz, 1H), 8.22 (s, 1H), 8.97 (s, 1H), 9.05 (s, 1H),10.47 (s, 1H).

Example 33 1a.dihydrochloride (1a.2HCl)

The compound 1a (1.27 g) was added to and dissolved in THF (38 mL), and4N hydrochloric acid-ethyl acetate solution (1.28 mL) was added dropwisewith stirring. The mixture was stirred overnight at room temperature andcollected by filtration. Drying gave the title compound as a white solid(1.17 g). This crude crystal (0.16 g) was suspended in isopropanol(IPA)-THF (1:1, 10 mL) and stirred in an oil bath at 70° C. The reactionmixture was allowed to stand to cool, and the product was collected byfiltration and dried under reduced pressure to give the title compoundas a crystalline powder (78 mg).

1a.2HCl: ¹H NMR (DMSO-d₆) δ ppm: 1.55 (s, 6H), 2.80 (s, 3H), 2.90-3.80(m, 8H), 5.90 (dd, 1H), 6.39 (dd, 1H), 6.70 (dd, 1H), 7.55 (t, 1H), 7.75(m, 1H), 8.05 (dd, 1H), 8.08 (s, 1H), 8.91 (s, 2H), 10.30 (s, 1H).

Elemental analysis: (Calcd. for C₂₇H₃₀Cl₃FN₆O.1.2IPA.0.5H₂O) C, 55.11;H, 5.39; Cl, 17.88; N, 14.13; (analyzed value) C, 55.26; H, 5.19; Cl,17.72; N, 14.12.

Example 34 1a.hydrochloride (1a.HCl)

The compound 1a (150 mg) was added to THF (3 mL) and the resultingsolution was ice-cooled. 4N Hydrochloric acid-ethyl acetate solution (81μL) was added dropwise with stirring. After stirring overnight at roomtemperature, the resulting product was collected by filtration and driedunder reduced pressure to give the title compound as a white solid (140mg).

1a.HCl: ¹H NMR (DMSO-d₆) δ ppm: 1.45 (s, 6H), 2.78 (s, 3H), 2.61 (m,2H), 3.02 (m, 2H), 3.10-3.75 (m, 4H), 5.85 (dd, 1H), 6.39 (dd, 1H), 6.70(dd, 1H), 7.58 (t, 1H), 6.80 (m, 1H), 7.92 (s, 1H), 8.20 (m, 1H), 8.65(s, 1H), 8.70(s, 1H), 10.10 (br. 3H).

Example 35 1a.dimesylate (1a.2MsOH)

The compound 1a (1.50 g) was added to and dissolved in THF (30 mL). 3Nmethanesulfonic acid (MsOH)-THF solution (1.99 mL) was added dropwisethereto with stirring at room temperature. After stirring overnight atroom temperature, THF (15 mL) was added and the resulting product wascollected by filtration and dried under reduced pressure to give thetitle compound as a white solid (1.98 g).

1a.2MsOH: ¹H NMR (DMSO-d₆) δ ppm: 1.48 (s, 6H), 2.34 (s, 6H), 2.81 (s,3H), 2.40-2.70 (m, 2H), 2.90-3.80 (m, 6H), 5.90 (dd, 1H), 6.39 (dd, 1H),6.55 (m, 1H), 7.54 (t, 1H), 7.75 (m, 1H), 7.95 (s, 1H), 8.10 (m, 1H),8.84. (s, 1H), 8.87 (br, 1H) 10.04 (s, 1H).

Example 36 1a.tosylate (1a.TsOH)

The compound 1 a(1.00 g) was dissolved in ethyl acetate (70 mL) and0.25N p-toluenesulfonic acid-ethyl acetate solution (8.27 mL) was addeddropwise with stirring at room temperature. After stirring for 2 hrs atroom temperature, and the resulting product was collected by filtrationand dried under reduced pressure to give the title compound as a whitesolid (1.23 g).

1a.TsOH: ¹H NMR (DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.28 (s, 3H), 2.50 (m,2H), 2.80 (s, 3H), 3.06 (m, 2H), 3.20-3.70 (m, 4H), 5.90 (d, 1H), 6.38(d, 1H), 6.60 (dd, 1H), 7.10 (d, J=7.9 Hz, 2H), 7.40-7.60 (m, 3H), 7.80(m, 1H), 7.92 (s, 1H), 8.10 (m, 1H), 8.70 (s, 1H), 8.79 (s, 1H), 9.35(br, 1H), 9.98 (s, 1H), 10.20 (br, 1H).

Example 37 1a.ethanedisulfonate [1a.CH₂SO₃H)₂]

The compound 1a (100 mg) was dissolved in acetone (4 mL), and 0.5Nethanedisulfonate-acetone solution (0.4 mL) was added dropwise withstirring at room temperature. After stirring overnight at roomtemperature, the resulting product was collected by filtration and driedunder reduced pressure to give the title compound as a white solid (89mg).

1a.

CH₂SO₃H)₂: ¹H NMR (DMSO-d₆). δ ppm: 1.46 (s, 6H), 2.60 (m, 2H),2.70-2.90 (m, 7H), 2.90-3.80 (m, 6H), 5.90 (d, 1H), 6.38 (d, 1H), 6.60(dd, 1H), 7.50 (t, 1H), 7.86 (m, 1H), 7.97 (s, 1H), 8.12 (m, 1H), 8.76(s, 2H), 9.40 (br, 1H), 10.03 (s, 1H), 10.50 (br, 1H).

Example 38 1a.diethanedisulfonate [1a.2CH₂SO₃H)₂]

The compound 1a (100 mg) was dissolved in acetone (2 mL) and 0.5Nethanedisulfonate-acetone solution (0.8 mL) was added dropwise withstirring at room temperature. After stirring overnight at roomtemperature, the resulting product was collected by filtration and driedunder reduced pressure to give the title compound as a white solid (122mg).

1a.2

CH₂SO₃H)₂: ¹H NMR (DMSO-d₆) δ ppm: 1.60 (d, J=2.6, 6H), 2.70-3.00 (m,13H), 3.20 (m. 2H), 3.60 (m, 4H), 5.40 (d, 1H), 6.60 (dd, 1H), 7.60 (t,1H), 7.70 (m, 1H), 8.00 (s, 1H), 8.10(d, 1H), 8.92 (s, 1H), 9.00 (s,1H), 9.80 (br, 1H), 10.20 (s, 1H).

Example 39 1a.dibenzenesulfonate (1a.2PhSO₃H)

The compound 1a (100 mg) was dissolved in acetone (3 mL) and 0.5Nbenzenesulfonic acid-acetone solution (0.8 mL) was added dropwise withstirring at room temperature. After stirring overnight at roomtemperature, the resulting product was collected by filtration and driedunder reduced pressure to give the title compound as a white solid (60mg).

1a.2PhSO₃H: ¹H NMR (DMSO-d₆) δ ppm: 1.49 (s, 6H), 2.60 (m, 2H), 2.81 (s,3H), 3.10 (m, 2H), 3.30 (d, 2H) 3.50 (d, 2H), 5.90 (d, 1H), 6.39 (d,1H), 6.60 (dd, 1H) 7.32 (m, 6H), 7.60 (m, 5H), 7.75 (m, 1H), 7.92 (s,1H), 8.07 (m, 1H), 8.88 (s, 1H), 8.96 (s, 1H), 9.40 (br, 1H), 10.10 (s,1H).

Example 40 Preparation (1) of 1a.½hydrate (1a.½H₂O) type A crystal form

Acetone (126 mL) was added to compound 1a (9.00 g) and the mixture wasstirred with heating at an inner temperature of 53° C. After completedissolution of the solid, the solution was cooled to an innertemperature of 24° C. over 7 hrs with stirring. The precipitate wascollected by filtration, and the filtration residue was washed withacetone and dried under reduced pressure at 80° C. for 4 hrs to give thetitle compound as pale-yellow crystals (7.32 g, 81%).

The XRD pattern of this crystal is shown in FIG. 1, and this crystal istaken as type A crystal form. The characteristic peaks shown in FIG. 1are as follows. characteristic peak (2θ, ±0.2°)

7.1°, 10.6°, 11.9°, 12.2°, 13.8°, 17.3°, 18.4°IR (KBr) ν cm⁻¹: 3376,2809, 1676, 1628, 1562, 1535, 1497, 1421, 1213, 1177. melting point:131-133° C.

Elemental analysis: (calcd. for C₂₇H₂₈ClFN₆O.½H₂O) C, 62.85; H, 5.66; N,16.29; (analyzed value) C, 62.68; H, 5.58; N, 16.14.

Example 41 Preparation (2) of 1a.½H₂O type A crystal form

Toluene (3.0 mL) was added to compound 1a (150 mg) and the suspensionwas stirred at room temperature for 69 hrs. The suspension was filteredand the filtration residue was washed with toluene and dried underreduced pressure at 60° C. for 6 hrs to give the title compound aspale-yellowish white crystals (131 mg, 87%). The XRD pattern of thiscrystal showed a type A crystal form.

Example 42 Preparation (3) of 1a.½H₂O type a crystal form

THF (1.0 mL) was added to compound 1a (150 mg) and the mixture washeated to an inner temperature of about 70° C. After completedissolution of the solid, heptane (1.3 mL) was gradually added dropwisewith stirring, and the solution was cooled to room temperature. Theprecipitate was collected by filtration, and the filtration residue waswashed with THF-heptane (1:2) and dried under reduced pressure at 60° C.for 6 hrs to give the title compound as pale-yellowish white crystals(90.5 mg, 59% The XRD pattern of this crystal showed a type A crystalform.

Elemental analysis: (calcd. for C₂₇H₂₈ClFN₆₀.1/2H₂O) C, 62.85; H, 5.66;N, 16.29; (analyzed value) C, 62.68; H, 5.58; N, 16.14.

Example 43 Preparation (4) of 1a.½H₂O type a crystal form

Ethyl acetate (2.0 mL) was added to compound 1a (200 mg) and the mixturewas heated to an inner temperature of about 70° C. After completedissolution of the solid, heptane (3.0 mL) was gradually added dropwisewith stirring, and the solution was cooled to room temperature. Theprecipitate was collected by filtration, and the filtration residue waswashed with ethyl acetate-heptane (1:2) and dried under reduced pressureat 60° C. for 6 hrs to give the title compound as pale-yellowish whitecrystals (119 mg, 79%). The XRD pattern of this crystal showed a type Acrystal form.

Example 44 Preparation (1) of 1a.2TsOH type a crystal form

Ethanol (3.41 L) was added to the crude crystal (568.23 g) obtained bythe method of Example 31 and the mixture was stirred with heating to aninner temperature of 70° C. After complete dissolution of the solid, thesolution was cooled to an inner temperature of 26° C. over 16 hrs withstirring (rate of stirring about 90 rpm). The precipitate was collectedby filtration, and the filtration residue was washed with ethanol anddried under reduced pressure at 60° C. for 20 hrs and at 75° C. for 12hrs to give the title compound as pale-yellow crystals (488.57 g, 85%).

The XRD pattern of this crystal is shown in FIG. 2, and this crystal istaken as type A crystal form. The characteristic peaks shown in FIG. 2are as follows. characteristic peak (2θ, ±0.2°)

3.3°, 6.6°, 7.5°, 9.4°, 13.9°, 17.4°, 19.1° melting point: 208.5-210° C.

Elemental analysis: [calcd. for C₄₁H₄₄ClFN₆O₇S₂.1/2H₂O (1a.2TsOH.½H₂O)]C., 57.23; H, 5.27; N, 9.77;S, 7.45 (analyzed value) C, 57.05; H, 5.09;N, 9.74.; S,7.45

Example 45 Preparation (2) of 1a.2TsOH type a crystal form

Isopropyl alcohol (5.0 mL) was added to the crude crystal (148 mg)obtained by the method of Example 31 and the mixture was stirred withheating to an inner temperature of 80° C. After complete dissolution ofthe solid, the solution was cooled to room temperature with stirring.The precipitate was collected by filtration, and the filtration residuewas washed with isopropyl alcohol and dried under reduced pressure at60° C. for 6 hrs to give the title compound as pale-yellow crystals (133mg, 90%). The XRD pattern of this crystal showed a type A crystal form.

Example 46 Preparation (3) of 1a.2TsOH type a crystal form

THF (8.0 mL) was added to the crude crystal (107 mg) obtained by themethod of Example 31 and the suspension was stirred at room temperaturefor 65 hrs. The suspension was filtered and the filtration residue waswashed with THF and dried under reduced pressure at 60° C. for 3 hrs togive the title compound as pale-yellow crystals (97 mg, 90%). The XRDpattern of this crystal showed a type A crystal form.

Example 47 Preparation (4) of 1a.2TsOH type a crystal form

Acetonitrile (6.5 mL) was added to the crude crystal (147 mg) obtainedby the method of Example 31 and the mixture was heated to an innertemperature of about 70° C. with stirring. After complete dissolution ofthe solid, the solution was cooled to room temperature with stirring.The precipitate was collected by filtration, and the filtration residuewas washed with acetonitrile and dried under reduced pressure at 60° C.for 6 hrs to give the title compound as pale-yellow crystals (113 mg,77%). The XRD pattern of this crystal showed a type A crystal form.

Example 48 Preparation (5) of 1a.2TsOH type a crystal form

Ethanol (2.5 mL) was added to the crude crystal (158 mg) obtained by themethod of Example 31 and the mixture was heated to an inner temperatureof about 80° C. with stirring. After complete dissolution of the solid,ethyl acetate (8.0 mL) was added dropwise with stirring and the solutionwas cooled to room temperature. The precipitate was collected byfiltration, and the filtration residue was washed with ethanol:ethylacetate (1:5) and dried under reduced pressure at 60° C. for 6 hrs togive the title compound as pale-yellow crystals (125 mg, 79%). The XRDpattern-of this crystal showed a type A crystal form.

Example 49 Preparation (1) of 1a.3HCl.4H₂O type A crystal form

Methanol (310 mL) was added to the crude crystal (12.73 g) obtained bythe method of Example 32 and the mixture was heated to an oil bathtemperature of about 70°0 C. with stirring. After complete dissolutionof the solid, ethyl acetate (120 mL) was gradually added dropwise withstirring at the same temperature, and the solution was gradually cooledto room temperature with stirring. The precipitate was collected byfiltration, and dried under reduced pressure at 50° C. for 4 hrs. Theobtained crystals were pulverized in a mortar and maintained under 75%humidity at room temperature for three days to give the title compound(10.00 g) as colorless crystals.

The XRD pattern of this crystal is measured and this crystal shape istaken as type A crystal form.

Elemental analysis: [calcd. for C₂₇H₃₉Cl₄FN₆O₅ (1a.3HCl.4H₂O)] C, 47.10;H, 5.71; N, 12.21; Cl, 20.60; (analyzed value) C, 47.29; H, 4.67; N,12.31; Cl, 20.45. moisture analysis (Karl-Fisher method): (calcd.)10.46%; (analyzed value) 10.20% (moisture vaporization—coulometrictitration); 10.15% (volumetric method).

Example 50 Preparation (2) of 1a.3HCl.4H₂O type A crystal form

Methanol (17 mL) was added to the crude crystal (0.400 g) obtained bythe method of Example 32 and the mixture was heated to an oil bathtemperature of about 70° C. with stirring. After complete dissolution ofthe solid, the solution was gradually cooled to room temperature withstirring. The precipitate was collected by filtration, and dried underreduced pressure at 80° C. for 7 hrs to give the title compound (0.242g) as pale-yellow crystals. The XRD pattern of this crystal showed atype A crystal form.

Example 51 Preparation (3) of 1a.3HCl.4H₂O type A crystal form

Water (8.0 mL) was added to the crude crystal (0.400 g) obtained by themethod of Example 32 and the mixture was stirred at room temperature.After complete dissolution of the solid, acetone (50 mL) was added atroom temperature with stirring. The precipitate was collected byfiltration and dried under reduced pressure at 80° C. for 7 hrs to givethe title compound as colorless crystals (0.143 g). The XRD pattern ofthis crystal showed a type A crystal form.

Example 52 Preparation (4) of 1a.3HCl.4H₂O type A crystal form

Acetonitrile (6 mL) was added to the crude crystal (0.400 g) obtained bythe method of Example 32 and the mixture was stirred at room temperaturefor 2 hrs. The suspension was filtered and the obtained crystals weredried under reduced pressure at 80° C. for 7 hrs to give the titlecompound (0.300 g) as colorless crystals. The XRD pattern of thiscrystal showed a type A crystal form.

Example 53 Preparation (5) of 1a.3HCl.4H₂O type A crystal form

Water (2.0 mL) was added to the crude crystal (0.400 g) obtained by themethod of Example 32 and the mixture was heated to an oil bathtemperature at 70° C. with stirring. After complete dissolution of thesolid, this solution was added dropwise to acetone (30 mL). Theprecipitate was collected by filtration and dried under reduced pressureat 80° C. for 7 hrs to give the title compound as colorless crystals(0.313 g). The XRD pattern of this crystal showed a type A crystal form.

Example 54 1a.H₂SO₄

Ethyl acetate (80 mL) was added to 1a (1.09 g, 2.15 mmol) fordissolution and a solution (4.31 mL, 2.15 mmol), wherein ethyl acetatehad been added to concentrated sulfuric acid (0.68 ml L, 12.5 mmol) tothe total amount of 25 mL, was added thereto. The mixture was stirred atroom temperature for 15 hrs. The precipitated crystals were collected byfiltration, and the crystals were washed with ethyl acetate and dried invacuo at 60° C. for 4 hrs to give pale-yellow crude crystals (1.27 g,97.8%)

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (s, 6H), 2.79 (s, 3H), 2.90-3.50(m, 8H), 5.86 (dd, 1H), 6.34 (dd, 1H), 6.59 (dd, 1H), 7.46 (t, 1H),7.80-7.86 (m, 1H), 7.92 (s, 1H), 8.18 (dd, 1H), 8.63 (s, 1H), 8.69 (s,1H), 9.95 (s, 1H), 10.01 (br s, 1H).

Example 55 1a.1.5H₂SO₄.H₂O

Ethyl acetate (80 mL) was added to 1 a(1.08 g, 2.14 mmol) fordissolution and a solution (6.42 mL, 3.21 mmol), wherein ethyl acetatehad been added to concentrated sulfuric acid (0.68 ml L, 12.5 mmol) tothe total amount of 25 mL, was added thereto. The mixture was stirred atroom temperature for 18 hrs. The precipitated crystals were collected byfiltration, and the crystals were washed with ethyl acetate and driedunder reduced pressure at 70° C. for 3 hrs to give yellow crude crystals(1.34 g, 95.9%). To this crude crystal (889 mg, 1.36 mmol) was addedmethanol (44.4 mL), and the mixture was heated under reflux to allowdissolution. After stirring at room temperature for 3 hrs, the mixturewas allowed to cool to room temperature. The precipitated crystals werecollected by filtration and the obtained crystals were washed withmethanol and dried under reduced pressure at 70° C. for 2 hrs to giveyellow crystals (604 mg, 68.0%).

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.42 (s, 6H), 2.46-2.64 (m, 2H), 2.80(s, 3H), 2.95-3.11 (m, 2H), 3.16-3.34 (m, 2H), 3.40-3.54 (m, 2H), 5.89(dd, 1H), 6.36 (dd, 1H), 6.61 (dd, 1H), 7.52 (t, 1H), 7.73-7.79 (m, 1H),7.94 (s, 1H), 8.10 (dd, 1H), 8.80 (s, 2H), 10.04 (s, 1H), 10.75 (br s,1H).

Elemental analysis: (calcd. for 1a.1.5H₂SO₄.H₂O) C, 48.25; H, 4.95; N,12.50; S, 7.16; (analyzed value) C, 48.47; H, 4.95; N, 12.56; S, 7.11.

Synthetic Example 13 Synthesis of trifluoromethanesulfonic acid4-(3-acetylphenylamino)-7-methoxy-6-quinazolinyl ester (6a)

1) A solution (200 mL) of acetic acid 4-chloro-7-methoxy-6-quinazolinylester [described in U.S. Pat. Nos. 5,770,599 and 5,770,603] (3.74 g,14.8 mmol) and 3-aminoacetophenone (2.0 g, 14.8 mmol) in isopropanol washeated under reflux for 5 hrs. After allowing to stand to cool, theprecipitate was collected by filtration to give acetic acid4-(3-acetylphenylamino)-7-methoxy-6-quinazolinyl ester hydrochloride(4.78 g, yield as monohydrochloride 83%). To a solution (100 mL) of thiscompound (3.0 g, 7.74 mmol) in methanol was added 28% aqueous ammonia (2mL), and the mixture was stirred at room temperature for 4 hrs and thenrefluxed. The produced precipitate was collected by filtration and driedunder reduced pressure to give1-[3-(6-hydroxy-7-methoxy-4-quinazolinylamino)phenyl]ethanone (2.07 g,87%).2) A solution (20 mL) of1-[3-(6-hydroxy-7-methoxy-4-quinazolinylamino)phenyl]ethanone (870 mg,2.8 mmol) and pyridine (0.34 mL, 4.2 mmol) in acetonitrile was stirredon an ice bath and trifluoromethanesulfonic acid anhydride (0.57 mL, 3.4mmol) was added dropwise. The reaction solution was gradually warmed upto room temperature and, after stirring at room temperature for 2 hrs,the mixture was concentrated. Aqueous sodium hydrogen carbonate wasadded to the residue and the mixture was stirred at room temperature for30 min. The product was filtered and dried under reduced pressure togive the title compound 6a (1.20 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ ppm: 2.65 (s, 3H), 4.06 (s, 3H), 7.40 (s, 1H),7.53 (t, J=7.9 Hz, 1H), 7.76 (br d, J=7.8 Hz, 1H), 7.72-7.83 (m, 1H),7.91 (br s, 1H), 8.16 (br d, J=8.9 Hz, 1H), 8.24 (t, J=1.8 Hz, 1H), 8.75(s, 1H).

Synthetic Example 14 Synthesis of trifluoromethanesulfonic acid4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-quinazolinyl ester (6b)

In the same manner as in-Synthetic Example 13-2) and using4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol, the objective6-triflate compound 6b was obtained.

6b: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 4.07 (s, 3H), 7.45 (t, J=9.1 Hz,1H), 7.51 (s, 1H), 7.76 (m, 1H), 8.09 (dd, J=2.5, 6.8 Hz, 1H), 8.64 (s,1H), 8.68 (s, 1H), 9.94 (s, 1H).

Synthetic Example 15 Synthesis of trifluoromethanesulfonic acid4-(3-methoxyphenylamino)-7-methoxy-6-quinazolinyl ester (6c)

In the same manner as in Synthetic Example 13-2) and using4-(3-methoxyphenylamino)-7-methoxyquinazolin-6-ol, the objective6-triflate compound 6c (quantitative) was obtained.

6c: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 3.79 (s, 3H), 4.06 (s, 3H), 6.75(m, 1H), 7.34 (m, 2H), 7.44 (m, 1H), 7.51 (m, 1H), 8.61 (s, 1H), 8.74(s, 1H), 9.84 (br s, 1H).

Synthetic Example 16 Synthesis of trifluoromethanesulfonic acid4-(3-chloro-4-fluorophenylamino)-6-methoxy-7-quinazolinyl ester (6d)

1) Using 7-benzyloxy-4-chloro-6-methoxyquinazolin hydrochloride[described in Hennequin et al., J. Med. Chem. 1999, 42 (26), 5369-5389]and 3-chloro-4-fluoroaniline and in accordance with the above-mentionedmethod of Hennequin et al. or the method of Synthetic Example 13, thecompound was converted to7-benzyloxy-6-methoxy-4-quinazolinyl)-(3-chloro-4-fluorophenyl)aminehydrochloride (yield 83%). Trifluoroacetic acid (7 mL) was added to thiscompound (412 mg) and the mixture was heated under reflux for 90 min.After allowing to stand to cool, the reaction mixture was poured intoice water. The precipitate was collected by filtration, and thefiltration residue was dissolved in methanol and dilute aqueous ammoniawas added until alkalified. The precipitate was collected by filtration,washed with water and diethyl ether and dried under reduced pressure togive 4-(3-chloro-4-fluorophenylamino)-6-methoxyquinazolin-7-ol(quantitative). This compound was reacted in the same manner as inSynthetic Example 13-2). After the completion of the reaction, thereaction mixture was poured into 1N aqueous hydrochloric acid andextracted with ethyl acetate. The organic layer was washed with water,aqueous sodium hydrogen carbonate and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(hexane-ethyl acetate) to give the objective 7-triflate compound 6d(66%).

6d: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 4.09 (s, 3H), 7.49 (t, J=9.1 Hz,1H), 7.78 (m, 1H), 7.91 (s, 1H), 8.10 (dd, J=2.5, 6.8 Hz, 1H), 8.20 (s,1H), 8.61 (s, 1H), 9.92 (s, 1H).

Synthetic Example 17 Synthesis of trifluoromethanesulfonic acid4-(3-chloro-4-fluorophenylamino)-7-ethoxy-6-quinazolinyl ester (6e)

1) 6,7-Diethoxy-3H-quinazolin-4-one (120.9 g, 516 mmol) was added tomethanesulfonic acid (723 mL), and L-methionine (88.53 g, 593 mmol) wasgradually added over 10 min period at an inner temperature of 59 to 71°C. After stirring at 80° C. to 104° C. for 11 hrs, the mixture wasallowed to stand to cool. Water (3 L) and then 48% aqueous sodiumhydroxide solution (930 g) were added. The precipitate was collected byfiltration and washed with water (200 mL×2) to give7-ethoxy-6-hydroxy-3H-quinazolin-4-one (97.45 g, 473 mmol, 92%).2) 7-Ethoxy-6-hydroxy-3H-quinazolin-4-one (106.4 g, 516 mmol) was addedto acetic anhydride (825 mL) and the mixture was stirred at an innertemperature of 88° C. Pyridine (107 mL) was added dropwise over 10 min,and the mixture was then stirred at an inner temperature of 98° C. to103° C. for 1.5 hrs. After allowing to stand to cool, ice water (3 L)was added, and the product was collected by filtration and washed withwater (50 mL×4). Methanol (400 mL) and 1N sodium hydroxide (100 mL) wereadded to the crystal and the mixture was stirred for 5 min. Theresulting crystals were collected by filtration and combined with thecrystals obtained by the first filtration to give the objective aceticacid 7-ethoxy-4-oxo-3,4-dihydroquinazolin-6-yl ester (49.3 g, 39%).3) To the above-mentioned ester compound (60.14 g, 242 mmol) were addeddropwise thionyl chloride (810 mL) and DMF (16.8 mL) at an innertemperature of 16° C. to 21° C. and the mixture was stirred at an innertemperature of 63° C. to 65° C. for 2 hrs. After allowing to stand tocool, the reaction mixture was concentrated, and toluene (500 mL) wasadded and the mixture was concentrated. This step was repeated twice.The residue was dissolved in chloroform (300 mL), washed with saturatedaqueous sodium hydrogen carbonate (250 mL×1, 300 mL×1) and dried. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give acetic acid4-chloro-7-ethoxy-6-quinazolinyl ester (29.2 g, 45%).4) Isopropanol (250 mL) and 3-chloro-4-fluoroaniline (5.86 g, 40.3 mmol)were added to acetic acid 4-chloro-7-ethoxy-6-quinazolinyl ester (10 g,40.3 mmol) and the mixture was stirred at an oil bath temperature of 90°C. for 2 hrs. After allowing to stand to cool, the product was collectedby filtration, dried and added to methanol (120 mL). 28% Aqueous ammonia(12 mL) was added, and after stirring at room temperature, water (200mL) was added. The precipitated product was collected by filtration,washed with water (100 mL), and dried under reduced pressure to give4-(3-chloro-4-fluoro-phenylamino)-7-ethoxyquinazolin-6-ol (10.65 g,79%).

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.44 (t, J=6.9 Hz, 3H), 4.34 (q, J=6.9Hz, 2H), 7.19 (s, 1H), 7.41 (t, J=6.9 Hz, 1H), 7.80 (s, 1H), 7.83 (m,1H), 8.22 (dd, J=2.5, 6.9 Hz, 1H), 8.47 (s, 1H), 9.48 (s, 1H), 9.60 (brs, 1H).

5) A solution (350 mL) of4-(3-chloro-4-fluoro-phenylamino)-7-ethoxyquinazolin-6-ol (10.5 g, 31.5mmol) in acetonitrile was stirred on an ice bath, and pyridine (4.13 mL,51.1 mmol) and trifluoromethanesulfonic anhydride (7.95 mL, 47.3 mmol)were added. The mixture was stirred at room temperature for 15 hrs.

The mixture was concentrated under reduced pressure to an about halfamount and water (700 mL) and methanol (200 mL) were added. Theresulting solid was collected by filtration and dried under reducedpressure to give the title compound 6e (9.8 g, 67%) as a white solid.

6e: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.42 (t, J=6.9 Hz, 3H) 4.35 (q,J=6.9 Hz, 2H), 7.48 (t, J=9.1 Hz, 1H), 7.50 (s, 1H), 7.76 (m, 1H), 8.11(m, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 9.98 (s, 1H).

Example 56

Nitrogen was bubbled into a solution (20 mL) of 6-triflate compound 6b(5.63 g, 12.46 mmol) and compound 4a (2.49 g, 14.95 mmol) in DMF for 10min. and triethylamine (4.30 mL, 31.15 mmol),tetrakis(triphenylphosphine)palladium (283 mg) and copper iodide(I) (95mg) were added. The mixture was stirred at 50° C. for 1 hr. The mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column (chloroform-methanol) and recrystallized fromacetonitrile-water to give the objective coupling compound 1ba (2.71 g,46%) as white crystals.

1ba: ¹H NMR (300MHz, CDCl₃) δ ppm: 1.52 (s, 6H), 2.32 (s, 3H), 2.57 (brs, 4H), 2.85 (br s, 4H), 3.98 (s, 3H), 7.16 (t, J=8.7 Hz, 1H), 7.18 (s,1H), 7.61 (m, 1H), 7.97 (dd, J=2.6, 6.6 Hz, 1H), 8.06 (br s, 1H), 8.18(s, 1H), 8.65 (s, 1H).

Example 57

Using 6-triflate compound 6b and compound 4c and in the same manner asin Example 56, compound 1bb (yield 66%) was obtained as a white-palepink crystalline powder.

1bb: ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.52 (s, 6H), 1.87 (s, 3H),2.60-2.80 (m, 8H), 3.54 (s, 2H), 3.98 (s, 3H), 7.17 (t, J=8.6 Hz, 1H),7.19 (s, 1H), 7.54 (m, 1H), 7.60 (br s, 1H), 7.94 (dd, J=2.6, 6.5 Hz,1H), 8.00 (s, 1H), 8.67 (s, 1H).

Example 58

Using 6-triflate compound 6b and 4-(1,1-dimethyl-2-propynyl)piperazine(see Synthetic Example 9) and in the same manner as in Example 56, thereaction was carried out. The reaction mixture was concentrated underreduced pressure and partitioned between chloroform-aqueous sodiumhydrogen carbonate. The organic layer was concentrated under reducedpressure. The purified crude substance was suspended in acetonitrile,stirred and the obtained solid collected by filtration was purified bysilica gel column chromatography to give the objective compound 1bc(yield 73%).

1bc: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.45 (s, 6H), 2.83 (br s, 4H),3.11 (br s, 4H), 3.97 (s, 3H), 7.22 (s, 1H), 7.42 (t, J=9.1 Hz, 1H),7.81 (m, 1), 8.16 (m, 1H), 8.56 (s, 1H), 8.58 (s, 1H), 9.83 (s, 1H).

4-(1,1-dimethyl-2-propynyl)piperazine (synthesized according to themethod of Synthetic Example 1 using an excess of piperazine (2.5equivalent amount) as a starting material, yield 42%): ¹H NMR (300 MHz,DMSO-d₆) δ ppm: 1.39 (s, 6H), 2.30 (s, 1H), 2.61 (br s, 4H), 2.93 (m,4H).

Example 59

A solution (5 mL) of compound 1bc (200 mg, 0.44 mmol), propyl bromide(40 μL, 0.44 mmol) and potassium carbonate (183 mg, 1.32 mmol) in DMFwas stirred with heating at 60 to 70° C. Propyl bromide was sequentiallyadded (16 μL×2), and after stirring with heating for the total of 3 hrs,ethyl acetate and aqueous ammonium chloride solution were added. Theorganic layer was dried and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(chloroform-methanol). A fraction containing the product wasconcentrated and suspended in acetonitrile-water, and after stirring,the resulting product was collected by filtration to give the objectivecompound 1bd (173 mg, 79%).

1bd: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 0.85 (t, J=7.4 Hz, 3H), 1.30-1.50(m, 2H), 1.42 (s, 6H), 2.21 (t, J=7.4 Hz, 2H), 2.41 (br s, 4H), 2.69 (brs, 4H), 3.97 (s, 3H), 7.22 (s, 1H), 7.44 (t, J=9.3 Hz, 1H), 7.83 (m,1H), 8.18 (dd, J=2.4, 6.9 Hz, 1H), 8.57 (s, 1H), 8.57 (s, 1H), 9.86 (brs, 1H).

Example 60

Using compound 1bc and isobutyl iodide and in the same manner as inExample 59, the compound was converted to the objective compound 1b(yield 48%).

1be: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 0.85 (d, J=6.3 Hz, 6H), 1.43 (s,6H), 1.76 (m, 1H), 2.04 (m, 2H), 2.39 (br s, 4H), 2.70 (br s, 4H), 2.70(br s, 4H), 4.02 (s, 3H), 7.22 (s, 1H), 7.44 (t, J=9.0 Hz, 1H), 7.84 (m,1H), 8.19 (m, 1H), 8.57 (s, 2H), 9.86 (s, 1H).

Example 61

A solution (5 mL) of compound 4a (0.44 g, 2.65 mmol) in dichloromethanewas stirred under ice-cooling and a 1M solution (2.7 mL, 2.7 mmol) of4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pin-BH) in THF and RhCl(PPh₃)₃(25 mg) were added thereto. After stirring at room temperature for 7hrs, a 1M THF solution (2.7 mL, 2.7 mmol) of pin-BH was added. Afterstirring overnight, a 1M THF solution (2.7 mL, 2.7 mmol) of pin-BH wasadded. After stirring for 9 hrs, the mixture was cooled to −10° C. andaqueous sodium hydrogen carbonate was added. The mixture was extractedwith diethyl ether (40 mL×1, 10 mL×1), dried and concentrated. Thecompound 6d (452 mg, 1.0 mmol), PdCl₂ (dppf).CH₂Cl₂[dppf=1,1′-bis(diphenylphosphino)ferrocene] (27 mg, 0.03 mmol), 2Maqueous sodium carbonate solution (4.5 mL) and DMF (6 mL) were added tothe obtained oil (1.08 g). This mixture was subjected several times tothe step of degassing and displacement with nitrogen. The mixture wasstirred at 80° C. for 1 hr. The reaction mixture was allowed to warm toroom temperature, and water (30 mL) was added. The product was extractedwith ethyl acetate (30 mL×3). The organic layer was washed withsaturated brine (20 mL), dried and concentrated. Diethyl ether was addedto the residue and insoluble material was filtered off. The filtrate wasconcentrated to give the objective 1bf (115 mg, 25%) as an oil. This wasdissolved in diethyl ether (4 mL) and 4N hydrochloric acid/ethyl acetate(61 μL) was added under ice-cooling. The mixture was stirred at roomtemperature for a while and the precipitate was collected by filtrationto give 1bf.hydrochloride (68 mg, yield 55% as monohydrochloride) as apale-yellow powder.

1bf.HCl: ¹H NMR (300 MHz, CDCl₃+D₂O) δ ppm: 1.50 (s, 6H), 2.70 (s, 3H),2.80-3.60 (m, 8H), 3.97 (s, 3H), 6.67 (d, J=16.2 Hz, 1H), 6.90 (d,J=16.2 Hz, 1H), 7.12 (t, J=8.8 Hz, 1H), 7.30 (s, 1H), 7.71 (m, 1H), 8.02(dd, J=2.4, 6.6 Hz, 1H), 8.57 (s, 1H), 8.72 (s, 1H), 9.70 (br s, 1H).

Example 62

Using compound 6a and compound 4a and in the same manner as in Example56, the objective product compound 1bg (yield 59%) was obtained.

1bg: ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.53 (s, 6H), 2.31 (s, 3H), 2.55 (brs, 4H), 2.65 (s, 3H), 2.84 (br s, 4H), 3.99 (s, 3H), 7.20 (s, 1H), 7.52(t, J=7.9 Hz, 1H), 7.74 (br d, J=7.7 Hz, 1H), 7.78 (br s, 1H), 8.05 (s,1H), 8.16 (dd, J=2.1, 8.1 Hz, 1H), 8.69 (s, 1H).

Example 63

Using compound 6c and compound 4a and in the same manner as in Example56, the objective product compound 1bh (yield 68%) was obtained.

1bh: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.43 (s, 6H), 2.16 (s, 3H), 2.37(br s, 4H), 2.69 (br s, 4H), 3.78 (s, 3H), 3.96 (s, 3H), 6.70 (dd,J=2.2, 8.2 Hz, 1H), 7.20 (s, 1H), 7.28 (t, J=8.2 Hz, 1H), 7.42-7.55 (m,2H), 8.54 (s, 1H), 8.60 (s, 1H), 9.72 (br s, 1H).

Examples 64, 65

Using compound 6d and compounds 4a and 4c and in the same manner as inExample 56, they were converted to the objective product compounds 1bi,1bj, respectively.

Example 64

1bi: yield 78%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.43 (s, 6H), 2.18 (s,3H), 2.40 (br s, 4H), 2.68 (br s, 4H), 4.00 (s, 3H), 7.47 (t, J=9.2 Hz,1H), 7.75 (S, 1H), 7.81 (m, 1H), 7.88 (s, 1H), 8.13 (dd, J=2.7, 6.6 Hz,1H), 8.54 (s, 1H), 9.77 (s, 1H).

Example 65

1bj: yield 78%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.44 (s, 6H), 2.56 (brs, 4H), 2.73 (br s, 4H), 3.73 (s, 2H), 4.00 (s, 3H), 7.47 (t, J=9.2 Hz,1H), 7.76 (s, 1H), 7.81 (m, 1H), 7.88 (s, 1H), 8.13 (dd, J=2.4, 6.9 Hz,1H), 8.54 (s, 1H), 9.77 (s, 1H).

Example 66

A solution of amino compound 2c (700 mg, 1.46 mmol) obtained by themethod of Example 3 in pyridine (7 mL) was cooled to 0° C. to 50° C. andmethanesulfonyl chloride (125 μL, 1.61 mmol) was gradually addeddropwise. The reaction vessel was naturally warmed while placed in anice bath, and the reaction mixture was poured into aqueous sodiumhydrogen carbonate. The precipitated solid was collected by filtrationand washed with cold water. The obtained purified crude substance wassubjected to silica gel column chromatography (chloroform-methanol) andthe obtained compound was suspension-washed with acetonitrile. Theproduct was collected by filtration and dried under reduced pressure togive the objective compound 1ca (552 mg, 68%).

1ca: yield 68%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 2.55 (brs, 4H), 2.74 (br s, 4H), 3.12 (s, 3H), 3.73 (s, 2H), 7.47 (t, J=9.2 Hz,1H), 7.80 (m, 1H), 7.85 (s, 1H), 8.13 (dd, J=2.7, 7.0 Hz, 1H), 8.46 (s,1H), 8.62 (s, 1H), 10.09 (s, 1H).

Examples 67-77

In the same manner as in Example 66, the compounds were synthesized fromthe corresponding amino compound 2.

Example 67

1cb: yield 24%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.20 (s, 3H), 2.40 (brs, 4H), 2.60 (br s, 4H), 3.11 (s, 3H), 3.61 (s, 2H), 7.47 (t, J=9.1 Hz,1H), 7.79 (m, 1H), 7.86 (s, 1H), 8.12 (dd, J=2.4, 6.8 Hz, 1H), 8.42 (s,1H), 8.60 (s, 1H), 10.07 (s, 1H).

Example 68

1cc: yield 45%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.59 (m, 4H), 3.13 (s,3H), 3.63 (m, 6H), 7.47 (t, J=9.1 Hz, 1H), 7.79 (m, 1H), 7.89 (s, 1H),8.13 (dd, J=2.4, 6.8 Hz, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 10.10 (s, 1H).

Example 69

1cd: yield 32%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.55 (s, 6H), 2.40 (m,4H), 3.00 (m, 4H), 3.12 (s, 3H), 7.47 (t, J=9.0 Hz, 1H), 7.79 (m, 1H),7.88 (s, 1H), 8.12 (br d, J=6.3 Hz, 1H), 8.45 (s, 1H), 8.62 (s, 1H),10.10 (s, 1H).

Example 70

1ce: yield 49%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 2.25-2.80 (m, 8H), 3.11(s, 3H), 3.58 (br s, 4H), 7.44 (t, J.=8.9 Hz, 1H), 7.79 (m, 2H), 8.11(m, 2H), 8.43 (s, 1H), 8.58 (s, 1H), 10.06 (s, 1H).

Example 71

1cf: yield 54%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.02 (s, 6H), 2.05 (s,3H), 2.18 (br s, 4H), 2.51 (br s, 4H), 3.06 (s, 3H), 5.89 (d, J=12.9 Hz,1H), 6.67 (d, J=12.9 Hz, 1H), 7.47 (t, J=9.0 Hz, 1H), 7.81 (m, 1H), 7.95(s, 1H), 8.14 (br d, J=6.5 Hz, 1H), 8.34 (s, 1H), 8.60 (s, 1H), 9.99 (s,1H).

Example 72

1cg: yield 62%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.20 (s,3H),2.43 (br s, 4H), 2.71 (br s, 4H), 3.10 (s, 3H), 7.46 (t, J=9.2 Hz,1H), 7.79 (m, 1H), 7.82 (s, 1H), 8.13 (dd, J=2.4, 6.8 Hz, 1H), 8.41 (s,1H), 8.60 (s, 1H), 10.06 (s, 1H).

Example 73

1ch: yield 29%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.01 (t, J=7.3 Hz, 3H),1.46 (s, 6H), 2.35 (q, J=7.3 Hz, 2H), 2.50 (br s, 4H), 2.72 (br s, 4H),3.09 (s, 3H), 7.46 (t, J=9.2 Hz, 1H), 7.81 (br s, 2H), 8.12 (dd, J=2.4,6.5 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 10.04 (s, 1H).

Example 74

1ci: yield 56%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (s, 6H), 1.82 (m,2H), 2.36 (s, 3H), 2.70 (m, 4H), 2.91 (m, 4H), 3.06 (s, 3H), 7.45 (t,J=9.2 Hz, 1H), 7.77 (br s, 2H), 8.11 (br d, J=7.0 Hz, 1H), 8.29 (s, 1H),8.55 (s, 1H), 9.98 (s, 1H).

Example 75

1cj: yield 46%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.49 (s, 6H), 1.71 (m,4H), 2.03 (m, 2H), 2.19 (s, 3H), 2.34 (s, 3H), 2.85 (br d J=11.3 Hz,2H), 3.00 (m, 1H), 3.07 (s, 3H), 7.46 (t, J=9.2 Hz, 1H), 7.73 (s, 1H),7.80 (m, 1H), 8.12 (br d, J=6.8 Hz, 1H), 8.34 (s, 1H), 8.58 (s, 1H),10.02 (s, 1H).

Example 7.6

1ck: yield 24%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 2.17 (s, 3H), 2.36 (brs, 4H), 2.50 (br s, 4H), 2.69 (m, 4H), 3.10 (s, 3H), 7.46 (t, J=9.2 Hz,1H), 7.80 (br s, 2H), 8.13 (dd, J=2.4, 6.8 Hz, 1H), 8.42 (s, 1H), 8.59(s, 1H), 10.06 (s, 1H).

Example 77

1cl: yield 31%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.47 (s, 6H), 2.87 (t,J=6.6 Hz, 4H), 3.11 (s, 3H), 3.26 (s, 6H), 3.25-3.51 (m, 4H), 7.47 (t,J=9.2 Hz, 1H), 7.80 (m, 1H), 7.84(s, 1H), 8.13 (dd, J=2.7, 7.0 Hz, 1H),8.45 (s, 1H), 8.62 (s, 1H), 9.40-9.60 (br s, 1H), 10.09 (s, 1H).

Example 78

1) Formamidine acetate (4.51 g, 43.3 mmol) and methoxyethanol (60 mL)were added to 5-bromo-4-nitroanthranyl acid (described inJP-A-2000-169451) (5.65 g, 21.7 mmol) and the mixture was refluxed for 4hrs. Water was added until the reaction mixture becomes about 200 mL andthe precipitate was filtered and washed with water. The precipitate wasdried under reduced pressure to give 6-bromo-7-nitro-3H-quinazolin-4-one(5.21 g, 64%). To a solution (20 mL) of6-bromo-7-nitro-3H-quinazolin-4-one (1.34 g, 5.0 mmol) in toluene wereadded phosphorous oxychloride (0.70 mL, 7.5 mmol) anddiisopropylethylamine (1.29 mL, 7.5 mmol), and the mixture was stirredat 80° C. for 5 hrs. A solution (5 mL) of 3-chloro-4-fluoroaniline (1.09g, 7.5 mmol) in isopropanol was added at room temperature, and themixture was stirred overnight. The reaction mixture was poured intohexane (30 mL) and the mixture was stirred at room temperature for 30min. The product was collected by filtration and dried. To this compoundwere added reduced iron (1.10 g, 20.0 mmol), 1N hydrochloric acid (10mL) and ethanol (30 mL) and the mixture was refluxed for 1 hr. 1NAqueous sodium hydroxide solution (10 mL) was added and the mixture wasstirred at 50° C. for 30 min. Saturated brine was added and the mixturewas extracted with ethyl acetate. The organic layer was concentrated andthe residue was suspension-washed with acetonitrile (10 mL) to give6-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,7-quinazolinediamine (5′) (987mg, 54%).

5′: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 6.24 (br s, 2H), 7.00 (s, 1H), 7.42(br t, 1H), 7.79 (br s, 1H), 8.17 (br s, 1H), 8.43 (s, 1H), 8.68 (s,1H), 9.64 (s, 1H).2) Using this compound 5′ and compound 4a and in the same manner as inExample 3,N⁴-(3-chloro-4-fluorophenyl)-6-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-4,7-quinazolinediamine(2a′) (yield 68%) was obtained.

2a′: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.47 (s, 6H), 2.67 (s, 3H), 5.99(s, 1H), 6.90 (s, 1H), 7.38 (t, J=9.2 Hz, 1H), 7.80 (m, 1H), 8.15 (dd,J=2.6, 6.8 Hz, 1H), 8.37 (s, 1H), 8.44 (s, 1H), 9.65 (br s, 1H).3) To a solution (4 mL) of 2a′ (200 mg, 0.44 mmol) in pyridine was addedmethanesulfonyl chloride (80 μL, 1.0 mmol) and the mixture was stirredat room temperature for 4.5 hrs. Then, methanesulfonyl chloride (80 μL,1.0 mmol) was added. After stirring overnight, methanesulfonyl chloride(80 μL, 1.0 mmol) was further added, and 6 hrs later, the mixture wasconcentrated. Water was added and the mixture was extracted with ethylacetate (30 mL×2), dried and concentrated. The obtained solid wassuspension-washed with acetonitrile, and collected by filtration to givecompound 1cg′ (145 mg, 55%).

1cg′: TOF Mass: m/z=609 [M+1];

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.41 (s, 6H), 2.11 (s, 3H), 2.33 (br s,4H), 2.66 (br s, 4H), 3.61 (s, 6H), 7.46 (t, J=9.1 Hz, 1H), 7.78 (m,1H), 8.02 (s, 1H), 8.11 (m, 1H), 8.66 (s, 1H), 8.74 (s, 1H), 10.20 (brs, 1H).

Example 79

A solution of amino compound 2a (453 mg, 1.00 mmol) obtained by themethod of Synthetic Example 2, 3-methylthiopropionic acid chloride (152mg, 1.20 mmol) and triethylamine (167 μL, 1.20 mmol) in DMF (4.5 mL) wasstirred at room temperature for 19 hrs and then at 40° C. for 6 hrs. Thereaction mixture-was poured-into aqueous sodium hydrogen carbonate (100mL) and the mixture was extracted with ethyl acetate (100 mL×2). Theobtained organic layer was washed with saturated brine (100 mL×2) anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was subjected to silica gel columnchromatography (methylene chloride-methanol) and recrystallized fromethyl acetate to give the objective coupling compound 1af (120 mg, 22%).

1af: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.12 (s, 3H), 2.17(s, 3H), 2.38 (br s, 4H), 2.67 (br s, 4H), 2.74-2.83 (m, 4H), 7.46 (t,J=9.0 Hz, 1H), 7.80-7.85 (m, 2H), 8.17 (dd, J=6.9, 2.4 Hz, 1H), 8.62 (brs, 2H), 9.66 (s, 1H), 10.03 (s, 1H).

Example 80

A solution of amino compound 2a (452 mg, 1.00 mmol) obtained by themethod of Synthetic Example 2, tetronic acid (126 mg, 1.50 mmol), sodiumhydrogen carbonate (423 mg, 5.00 mmol) and HATU (701 mg, 1.84 mmol) inDMF (1.0 mL) was stirred at room temperature for 20 hrs. The reactionmixture was poured into aqueous sodium hydrogen carbonate (100 mL) andthe mixture was extracted with ethyl acetate (50 mL×2). The obtainedorganic layer was washed with saturated brine (50 mL×2) and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the residue was subjected to silica gel columnchromatography (methylene chloride-methanol), and suspension-washed withethyl acetate to give the objective coupling compound lag (71 mg, 14%).

1ag: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.45 (s, 6H), 2.06 (s, 3H), 2.15(s, 3H), 2.37 (br s, 4H), 2.67 (br s, 4H), 7.46 (t, J=9.0 Hz, 1H),7.81-7.85 (m, 2H), 8.19 (dd, J=6.3, 1.8 Hz, 1H), 8.54 (s, 1H), 8.63 (s,1H), 9.98 (s, 1H), 10.26 (s, 1H).

Example 81

A solution of amino compound 2a (452 mg, 1.00 mmol) obtained by themethod of Synthetic Example 2, and ketene dimer (220 mg, 2.61 mmol) intoluene (15 mL) were refluxed at room temperature for 1.5 hrs. Thereaction mixture was concentrated and subjected to silica gel columnchromatography (methylene chloride-methanol) to give the objectivecoupling compound 1ah (110 mg, 20%).

1ah: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.21 (s, 3H), 2.27(s, 3H), 2.44 (br s, 4H), 2.67 (br s, 4H), 3.17 (s, 2H), 7.45 (t, J=9.3Hz, 1H), 7.78-7.83 (m, 2H), 8.14 (dd, J=6.9, 2.4 Hz, 1H), 8.60 (s, 1H),8.71 (s, 1H), 9.93 (s, 1H), 10.01 (s, 1H).

Example 82

A solution of amino compound 2a (452 mg, 1.00 mmol) obtained by themethod of Synthetic Example 2, cyanoacetic acid (425 mg, 5.00 mmol),triethylamine (209 μL, 1.50 mmol) and EDC (288 mg, 1.5 mmol) in DMF (5.0mL) was stirred at room temperature for 14 hrs. The reaction mixture waspoured into aqueous sodium hydrogen carbonate (100 mL) and extractedwith ethyl acetate (50 mL×2). The obtained organic layer was washed withsaturated brine (50 mL×2) and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was subjectedto silica gel column chromatography (methylene chloride-methanol) andfurther recrystallized from methanol to give the objective couplingcompound 1ai (189 mg, 37%).

1ai: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.34 (s, 3H), 2.64(br s, 4H), 2.74 (br s, 4H), 4.14 (s, 2H), 7.46 (t, J=9.0 Hz, 1H),7.80-7.86 (m, 2H), 8.19 (dd, J=6.6, 2.1 Hz, 1H), 8.59 (s, 1H), 8.64 (s,1H), 10.10 (s, 1H), 10.31 (s, 1H).

Example 83

A solution of amino compound 2a (905 mg, 2.00 mmol) obtained by themethod of Synthetic Example 2 and 2-chloroethanesulfonyl chloride (840μL, 8.00 mmol) in pyridine (5.0 mL) was stirred at room temperature for1 hr. The reaction mixture was poured into saturated brine (200 mL) andextracted with ethyl acetate (200 mL×2). The obtained organic layer waswashed with saturated brine (300 mL×3) and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas subjected to silica gel column chromatography (methylenechloride-methanol) and further subjected to pTLC (methylenechloride-methanol) to give the objective coupling compound 1aj (9 mg,0.8%).

1aj: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.29 (s, 3H), 2.55(br s, 4H), 2.77 (br s, 4H), 5.75 (s, 1H), 5.91 (d, j=9.9 Hz, 1H), 6.01(d, J=16.5 Hz, 1H), 6.85 (dd, J=16.4, 9.9 Hz), 7.45 (t, J=9.1 Hz, 1H),7.74-7.83 (m, 2H), 8.13 (dd, J=6.8, 2.2 Hz, 1H), 8.35 (s, 1H), 8.57 (s,1H), 10.00 (s, 1H).

Examples 84-87

Using mixtures (about 3:1) of 7-bromo-6-nitro-3H-quinazolin-4-one and7-bromo-8-nitro-3H-quinazolin-4-one and various anilines as startingmaterials and according to the method of Synthetic Example 2-1), themethod of Example 3-1) (simultaneously using compound 4a), the method ofSynthetic Example 5, and the method of Example 3-2), compounds 1ak-1anwere synthesized (Scheme 6).

wherein R¹ denotes a substituent such as m-OMe, m-CN, p-NMe₂, m-Me andthe like.

Example 84

Using 3-methoxyaniline as aniline, the compound was converted to theobjective compound 1ak (yield 40%).

1ak: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.42 (s, 6H), 2.15 (s, 3H), 2.35(br s, 4H), 2.63 (br s, 4H), 3.78 (s, 3H), 5.83 (dd, J=10.3, 1.7 Hz,1H), 6.32 (dd, J=17.0, 1.7 Hz, 1H), 6.57 (dd, J=17.0, 10.1 Hz, 1H), 6.72(dd, J=7.8, 2.2 Hz, 1H), 7.29 (t, J=8.2 Hz, 1H), 7.48-7.55 (m, 2H), 7.81(s, 1H), 8.60 (s, 1H), 8.71 (s, 1H), 9.81 (s, 1H), 9.83 (s, 1H).

Example 85

Using 3-aminobenzonitrile as aniline, the compound was converted to theobjective compound 1al (yield 11%).

1al: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.43 (s, 6H), 2.14 (s, 3H), 2.34(br s, 4H), 2.63 (br s, 4H), 5.84 (dd, J=10.3, 1.5 Hz, 1H), 6.33 (dd,J=17.1, 1.5 Hz, 1H), 6.58 (dd, J=17.0, 10.1 Hz, 1H), 7.57-7.64 (m, 2H),7.85 (s, 1H), 8.16 (d, J=7.1 Hz, 1H), 8.42 (s, 1H), 8.67 (s, 1H), 8.71(s, 1H), 9.88 (s, 1H), 10.12 (s, 1H).

Example 86

Using N,N′-dimethylbenzene-1,4-diaminobenzene as aniline, the compoundwas converted to the-objective compound 1am (yield 72%).

1am: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.42 (s, 6H), 2.14 (s, 3H), 2.35(br s, 4H), 2.63 (br s, 4H), 2.90 (s, 6H), 5.82 (br d, J=10.0 Hz, 1H),6.31 (br d, J=17.0 Hz, 1H), 6.57 (dd, J=17.0, 10.0 Hz, 1H), 6.76 (d,J=9.2 Hz, 2H), 7.56 (d, J=9.2 Hz, 2H), 7.75 (s, 1H), 8.46 (s, 1H), 8.63(s, 1H), 9.70 (s, 1H), 9.82 (s, 1H).

Example 87

Using m-tolylamine as aniline, the compound was converted to theobjective compound 1an (yield 63%).

1an: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.42 (s, 6H), 2.14 (s, 3H), 2.34(br s, 7H), 2.62 (br s, 4H), 5.83 (dd, J=10.0, 1.9 Hz, 1H), 6.31 (dd,J=17.3, 1.9 Hz, 1H), 6.58 (dd, J=17.3, 10.0 Hz, 1H), 6.96 (d, J=7.0 Hz,1H), 7.27 (m, 1H), 7.63 (br s, 2H), 7.80 (s, 1H), 8.57 (s, 1H), 8.70 (s,1H), 9.81 (s, 1H), 9.84 (s, 1H).

Example 88

To the triflate compound 6e (1.00 g, 2.15 mmol) prepared in SyntheticExample 17 were added compound 4b (395 mg, 2.58 mmol), triethylamine (16mL) and DMF (4 mL), and the mixture was repeatedly subjected to the stepof degassing and displacement with nitrogen. Palladium (II) acetate(48.2 mg) and triphenylphosphine (67.9 mg) were added. The mixture wasstirred at 80° C. for 5 hrs and concentrated under reduced pressure. 5%Aqueous sodium hydrogen carbonate and saturated brine were added to theresidue and the mixture was extracted with ethyl acetate. After dryingand concentration, the residue was purified [silica gel columnchromatography, suspension-washed with ethanol-water, and recrystallizedfrom THF-water] to give the objective coupling compound 1bk (434 mg,43%) as colorless crystals.

1bk: ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (s, 6H), 1.53 (t, J=7.0 Hz,3H), 2.80 (m, 4H), 3.80 (m, 4H), 4.18 (q, J=7.0 Hz, 2H), 7.17 (s, 1H),7.17 (t, J=8.8 Hz, 1H), 7.40 (br s, 1H), 7.54 (m, 1H), 7.92 (s, 1H),7.95 (dd, J=2.6, 6.3 Hz, 1H), 8.68 (s, 1H).

Examples 89-111

Using triflate compound 6e and various compounds 4, and in the samemanner as in Example 88, compounds 1 bi-1bah were synthesized. Thestructure, yield and spectrum data of the compounds are shown in thefollowing.

Example 89

1bl (yield 70%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (s, 6H), 1.51 (t,J=7.0 Hz, 3H), 2.43 (s, 3H), 2.82 (t, J=6.1 Hz, 2H), 3.39 (s, 3H), 3.54(t, J=6.1 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 7.15 (s, 1H), 7.16 (t, J=8.8Hz, 1H), 7.52 (br s, 1H), 7.56 (m, 1H), 7.92 (s, 1H), 7.95 (dd, J=2.7,6.5 Hz, 1H), 8.66 (s, 1H).

Example 90

1bm (yield 53%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (s, 6H), 1.53 (t,J=6.9 Hz, 3H), 2.42 (s, 3H), 2.59 (t, J=6.5 Hz, 2H), 3.01 (t, J=6.5 Hz,2H), 4.21 (q, J=6.9 Hz, 2H), 7.16 (t, J=8.8 Hz, 1H), 7.18 (s, 1H), 7.54(br s, 1H), 7.56 (m, 1H), 8.00 (dd, J=2.6, 6.3 Hz, 1H), 8.12 (s, 1H),8.67 (s, 1H).

Example 91

1bn (yield 55%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.40-1.60 (m, 11H),1.60-1.75 (m, 4H), 2.74 (m, 4H), 4.19 (q, J=6.9 Hz, 2H), 7.17 (t, J=8.6Hz, 1H), 7.17 (s, 1H), 7.34 (br s, 1H), 7.52 (m, 1H), 7.91 (br s, 1H),7.95 (dd, J=2.7, 6.5 Hz, 1H), 8.67 (s, 1H).

Example 92

1bo.nHCl [1bo was converted to its hydrochloride with hydrochloricacid/ethyl acetate (3 equivalent amount) in methanol-ethyl acetate(1:2)] (yield 41% when n=3): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.48 (t,J=6.9 Hz, 3H), 1.82 (br s, 6H), 2.89 (s, 6H), 2.92 (br s, 3H), 3.70 (brs), 4.30 (q, J=6.9 Hz, 2H), 7.47 (s, 1H), 7.55 (t, J=9.0 Hz, 1H), 7.83(m, 1H), 8.11 (dd, J=2.6, 2.7 Hz, 1H), 8.94 (s, 1H), 9.52 (br s, 1H).

Example 93

1bp (yield 48%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.43-1.47 (m, 3H),1.43 (s, 6H), 2.15 (s, 3H), 2.37 (br s, 4H), 2.71 (br s, 4H), 4.21 (q,J=6.8 Hz, 2H), 7.17 (s, 1H), 7.44 (t, J=9.2 Hz, 1H), 7.82 (m, 1H), 8.20(dd, J=2.7, 7.0 Hz, 1H), 8.55 (s, 1H), 8.56 (s, 1H), 9.84 (s, 1H).

Example 94

1bq (yield 23%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (t, J=7.0 Hz, 3H),1.55 (s, 6H), 1.79(m, 4H), 1.97 (m, 2H), 2.25 (s, 3H), 2.45(s, 3H), 2.90(m, 2H), 3.01(m, 1H), 4.19 (q, J=7.0 Hz, 2H), 7.17 (t, J=8.8 Hz, 1H),7.17 (s, 1H), 7.36 (br s, 1H), 7.53 (m, 1H), 7.86 (s, 1H), 7.94 (dd,J=2.7, 6.5 Hz, 1H), 8.67 (s, 1H).

Example 95

1br (yield 55%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.00-1.20 (m, 6H),1.40-1.60 (m, 9H), 2.80 (q, J=7.0 Hz, 4H), 4.18 (q, J=7.0 Hz, 2H), 7.16(t, J=8.8 Hz, 1H), 7.16 (s, 1H), 7.38 (br s, 1H),7.51 (m, 1H), 7.88 (s,1H), 7.94 (dd, J=2.7, 6.5 Hz, 1H), 8.66 (s, 1H).

Example 96

1bs (yield 31%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.53 (s, 6H), 1.53 (t,J=7.0 Hz, 3H), 2.73(m, 4H), 2.88 (m, 4H), 3.53 (s, 2H), 4.19 (q, J=7.0Hz, 2H), 7.13 (t, J=8.9 Hz, 1H), 7.13 (s, 1H), 7.39 (br s, 1H), 7.53 (m,1H), 7.93 (s, 1H), 7.95 (dd, J=2.7, 6.8 Hz, 1H), 8.67 (s, 1H).

Example 97

1bt (yield 14%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.26 (m, 1H), 1.50 (m,2H), 1.53 (t, J=7.0 Hz, 3H), 1.77(m, 5H), 2.17 (m, 2H), 2.32 (s, 3H),2.57(br s, 4H), 2.88(br s, 4H), 4.19 (q, J=7.0 Hz, 2H), 7.15 (s, 1H),7.17 (t, J=8.9 Hz, 1H), 7.65 (m, 1H), 8.01 (m, 2H), 8.17 (s, 1H), 8.65(s, 1H).

Example 98

1bu (yield 48%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.52 (s, 6H), 1.52 (t,J=7.0 Hz, 3H), 2.96 (t, J=6.8 Hz, 4H), 3.37(s, 6H), 3.51 (t, J=6.8 Hz,4H), 4.18 (q, J=7.0 Hz, 2H), 7.16 (s, 1H), 7.17 (t, J=8.9 Hz, 1H), 7.44(br s, 1H), 7.56 (m, 1H), 7.90 (s, 1H), 7.96 (dd, J=2.7, 6.8 Hz, 1H),8.66 (s, 1H).

Example 99

1bv (yield 23%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (m, 11H), 1.77(m, 2H), 2.35 (m, 2H), 2.99 (m, 2H), 3.40-3.50 (m, 1H), 4.21 (q, J=7.0Hz, 2H), 4.58 (d, J=4.3 Hz, 1H), 7.17 (s, 1H), 7.43 (t, J=9.2 Hz, 1H),7.84 (m, 1H), 8.20 (dd, J=2.7, 6.8 Hz, 1H), 8.54 (s, 1H), 8.56 (s, 1H),9.83 (s, 1H).

Example 100

1bw (yield 50%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.50 (s, 6H),1.52 (t,J=6.8 Hz, 3H), 1.88 (m, 2H), 2.37 (s, 3H), 2.65(m, 4H), 2.97 (m, 4H),4.18 (q, J=6.8 Hz, 2H), 7.15 (s, 1H), 7.16 (t, J=8.9 Hz, 1H), 7.56 (m,1H), 7.72 (br s, 1H), 7.96 (dd, J=2.7, 6.8 Hz, 1H), 8.01 (s, 1H), 8.65(s, 1H).

Example 101

1bx (yield 59%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.51 (s, 6H), 1.53 (t,J=7.0 Hz, 3H), 2.49 (m, 4H), 2.58 (t, J=6.1 Hz, 2H), 2.99 (t, J=6.1 Hz,2H), 3.68 (m, 4H), 4.20 (q, J=7.0 Hz, 2H), 7.17 (t, J=8.9 Hz, 1H), 7.18(s, 1H), 7.48 (br s, 1H), 7.54 (m, 1H), 7.92 (s, 1H), 7.94 (dd, J=2.7,6.8 Hz, 1H), 8.68 (s, 1H).

Example 102

1by (yield 76%): ¹H NMR (270 MHz, CDCl₃) 8. ppm: 1.23 (t, J=7.0 Hz, 6H),1.50 (t, J=7.0 Hz, 3H), 2.29 (s, 3H), 2.50-2.60 (br s, 4H), 2.89 (br s,4H), 3.57-3.82 (m, 8H), 4.16 (q, J=7.0 Hz, 2H), 7.11 (s, 1H), 7.15(t,J=8.9 Hz, 1H), 7.62 (m, 1H), 7.99 (dd, J=2.7, 6.8 Hz, 1H), 8.27 (s, 1H),8.30 (s, 1H), 8.62 (s, 1H).

Example 103

1bz (yield 64%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.14 (t, J=7.0 Hz, 3H),1.52 (s, 6H), 1.53 (t, J=7.0 Hz, 3H), 2.46 (q, J=7.0 Hz, 2H), 2.50-2.60(br s, 4H), 2.88 (br s, 4H), 4.19 (q, J=7.0 Hz, 2H), 7.14 (s, 1H),7.16(t, J=8.9 Hz, 1H), 7.67 (m, 1H), 8.00 (dd, J=2.7, 6.5 Hz, 1H), 8.17(br s, 1H), 8.24 (s, 1H), 8.64 (s, 1H).

Example 104

1baa (yield 76%): ¹H NMR (270 MHz, CDCl₃) 5 ppm: 1.49 (t, J=7.0 Hz, 3H),1.51 (s, 6H), 2.10 (s, 3H),2.74 (m, 4H), 3.53 (m, 2H), 3.68 (m, 2H),4.14 (q, J=7.0 Hz, 2H), 7.15 (s, 1H), 7.16(t, J=8.9 Hz, 1H), 7.58 (m,1H), 7.92 (br s, 1H), 7.96 (dd, J=2.4, 6.5 Hz, 1H), 7.98 (s, 1H), 8.66(s, 1H).

Example 105

1bab (yield 47%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.14 (t, J=7.0 Hz, 3H),1.50 (s, 6H), 1.52 (t, J=7.0 Hz, 3H), 2.68 (m, 2H), 2.75 (q, J=7.0 Hz,2H), 3.13 (m., 2H), 3.71 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.16 (s, 1H),7.16(t, J=8.9 Hz, 1H), 7.68 (m, 1H), 7.79 (br s, 1H), 7.98 (dd, J=2.7,6.5 Hz, 1H), 8.10 (s, 1H), 8.67 (s, 1H).

Example 106

1bac (yield 8%): ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.53 (t, J=7.0 Hz, 3H),2.30 (s, 3H), 2.49 (br s, 4H), 2.64 (br s, 4H), 2.73 (m, 4H), 4.21 (q,J=7.0 Hz, 2H), 7.16 (s, 1H), 7.17(t, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.58(br s, 1H), 7.95 (dd, J=2.7, 6.5 Hz, 1H), 7.97 (s, 1H), 8.65 (s, 1H).

Example 107

1bad (yield 65%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (t, J=7.0 Hz,3H), 1.47 (s, 6H), 2.83 (br s, 4H), 2.89 (s, 3H), 3.17 (br s, 4H), 4.22(q, J=7.0 Hz, 2H), 7.18 (s, 1H), 7.44 (t, J=9.2 Hz, 1H), 7.82 (m, 1H),8.20 (dd, J=2.7, 6.8 Hz, 1H), 8.57 (s, 2H), 9.83 (s, 1H).

Example 108

1bae (yield 39%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (s, 6H), 1.46(t, J=7.0 Hz, 3H), 2.50 (br s, 4H), 2.54 (t, J=5.9 Hz, 2H), 2.67 (t,J=5.9 Hz, 2H), 2.73 (br s, 4H), 4.21 (q, J=7.0 Hz, 2H), 7.18 (s, 1H),7.44 (t, J=9.1 Hz, 1H), 7.82 (m, 1H), 8.20 (dd, J=2.7, 6.8 Hz, 1H), 8.57(s, 2H), 9.84 (s, 1H).

Example 109

1baf (yield 49%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (m, 11H), 1.89(m, 2H), 2.40 (m, 2H), 2.98 (m, 2H), 3.16 (m, 1H), 3.23 (s, 3H), 4.22(q, J=7.0 Hz, 2H), 7.18 (s, 1H), 7.44 (t, J=9.2 Hz, 1H), 7.83 (m, 1H),8.20 (dd, J=2.7, 6.8 Hz, 1H), 8.55(s, 1H), 8.56 (s, 1H), 9.83 (s, 1H).

Example 110

1bag (yield 64%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 0.97 (t, J=7.0 Hz,6H), 1.42 (t, J=7.0 Hz, 3H), 1.71 (m, 4H), 2.15 (s, 3H), 2.35 (br s,4H), 2.69 (br s, 4H), 4.21 (q, J=7.0 Hz, 2H), 7.17 (s, 1H), 7.44 (t,J=9.2 Hz, 1H), 7.81 (m, 1H), 8.17 (dd, J=2.7, 6.8 Hz, 1H), 8.54 (s, 1H),8.55 (s, 1H), 9.87 (s, 1H).

Example 111

1bah (yield 29%): ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.43 (s, 6H), 1.45(t, J=7.0 Hz, 3H), 2.42-2.52 (m, 4H), 2.44 (t, J=5.8 Hz, 2H), 2.71 (brs, 4H), 3.22 (s, 3H), 3.41 (t, J=5.8 Hz, 2H), 4.21 (q, J=7.0 Hz, 2H),7.17 (s, 1H), 7.44 (t, J=8.9 Hz, 1H), 7.83 (m, 1H), 8.20 (dd, J=2.7, 7.0Hz, 1H), 8.56 (s, 1H), 8.57 (s, 1H), 9.84 (s, 1H).

Synthetic Example 18 Synthesis of trifluoromethanesulfonic acid7-ethoxy-4-[3-(3-hydroxy-3-methyl-1-butynyl)phenylamino]-6-quinazolinylester (6f)

Isopropanol (10 mL)-dichloromethane (2 mL) was added to acetic acid4-chloro-7-ethoxy-6-quinazolinyl ester (400 mg, 1.50 mmol) withstirring, and 4-(3-aminophenyl)-2-methyl-3-butyn-1-ol (290 mg, 1.65mmol) was added. After 1.5 hours, hexane (50 mL) was added and themixture was concentrated. Isopropanol (10 mL)-dichloromethane (2 mL) wasadded to the residue and hexane (30 mL) was slowly added dropwise. Themixture was stirred under ice-cooling for 15 min. The product wascollected by filtration and dried under reduced pressure to give aceticacid(7-ethoxy-4-[3-(3-hydroxy-3-methyl-1-butynyl)phenylamino]-6-quinazolinylester (547 mg, 83%) as a yellow solid.

This ester compound (513 mg, 1.16 mmol) was dissolved in methanol (5 mL)and 28% aqueous ammonia (1 mL) was added at room temperature. Themixture was stirred and water (10 mL) was added. After stirring for 30min, the product was collected by filtration and dried under reducedpressure to give7-ethoxy-4-[3-(3-hydroxy-3-methyl-1-butynyl)phenylamino]quinazolin-6-ol(392 mg, 93%) as a colorless solid.

¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (t, J=7.0 Hz, 3H), 1.48 (s, 6H),4.24 (q, J=7.0 Hz, 2H), 5.51 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.18 (s,1H), 7.34 (t, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.99(s, 1H), 8.47 (s, 1H), 9.37 (s, 1H), 9.56 (br s, 1H).

In the same manner as in Synthetic Example 13-2), this compound wasconverted to the title compound (6f) (quantitative).

6f: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (t, J=7.0 Hz, 3H), 1.48 (s,6H), 4.41 (q, J=7.0 Hz, 2H), 7.35 (d, J=7.6 Hz, 1H), 7.46 (s, 1H), 7.51(t, J=8.0 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 8.88 (s, 1H),8.96 (s, 1H), 11.19 (br s, 1H).

Example 112

Using compound 6f and compound 4c and in the same manner as in Example88, a coupling compound was obtained (yield 76%). A suspension (21 mL)of this coupling compound (565 mg, 1.05 mmol) and potassium hydroxide(299 mg, 5.33 mmol) in toluene was stirred at 80° C. for 1 hr and underreflux for 1.5 hrs. The reaction mixture was concentrated and water wasadded to the residue. The mixture was extracted with ethyl acetate andthe extract was dried and concentrated and subjected to silica gelcolumn chromatography (ethyl acetate). The obtained solid wasrecrystallized from ethanol-water to give a compound 1bai (162 mg, 32%).

1bai : ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.40-1.50 (m, 9H), 2.56 (br s,4H), 2.77 (br s, 4H), 3.72 (s, 2H), 4.20 (s, 1H), 4.21 (q, J=7.0 Hz,2H), 7.17 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.92(d, J=8.1 Hz, 1H), 8.07 (m, 1H), 8.56 (s, 1H), 8.60 (s, 1H), 9.78 (br s,1H),

Examples 113-117

Using triflate compound 6f and various compounds 4, and in the samemanner as in Example 112, compounds 1baj-1ban were synthesized. Thestructure and spectrum data of the compounds are shown in the following.

Example 113

1baj : ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.44 (s, 6H), 1.45 (t, J=7.1 Hz,3H), 2.71 (m, 4H), 3.65 (m, 4H), 4.21 (s, 1H), 4.22 (q, J=7.1 Hz, 2H),7.18 (s, 1H), 7.22 (d, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.90 (d, 1H), 8.07(s, 1H), 8.57 (s, 1H), 8.60 (s, 1H), 9.79 (s, 1H).

Example 114

1bak: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.40 (t, J=7.0 Hz, 3H), 1.53 (s,6H), 2.01 (s, 3H), 2.81 (br s, 4H), 3.55 (br s, 4H), 4.21 (d, J=7.0 Hz,2H), 4.21 (s, J=7.0 Hz, 1H), 7.19 (s, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.41(t, J=7.9 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 8.60 (s, 1H),8.67 (s, 1H), 9.91 (br s, 1H).

Example 115

1bal: ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.42 (t, J=6.8 Hz, 3H), 1.49 (s,6H), 1.52-1.90 (m, 6H), 2.11 (s, 3H), 2.37 (s, 3H), 2.77 (br d, J=11.1Hz, 2H), 2.95 (s, 1H), 4.21 (s, 1H), 4.22 (q, 2H), 7.17 (s, 1H), 7.21(d, J=7.8 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.07(br s, 1H), 8.56 (s, 2H), 9.78 (br s, 1H).

Example 116

1bam: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.52 (s, 6H), 1.52 (t, J=7.0 Hz,3H), 2.31 (s, 3H), 2.55 (br s, 4H), 2.87 (br s, 4H), 3.09 (s, 1H), 4.19(q, J=7.0 Hz, 2H), 7.15 (s, 1H), 7.28 (d, 1H), 7.28 (d, 1H), 7.36 (t,1H), 7.80 (d, 1H), 7.91 (br s, 1H), 7.96 (s, 1H), 8.12 (s, 1H), 8.66 (s,1H).

Example 117

1ban : ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (m, 9H), 2.15 (s, 6H),2.25-2.40 (m, 5H), 2.62 (t, J=7.2 Hz, 2H), 4.21 (s, 1H), 4.22 (q, 2H),7.17 (s, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.92 (d,J=8.4 Hz, 1H), 8.08 (s, 1H), 8.56 (s, 1H), 8.60 (s, 1H), 9.79 (br s,1H).

Examples 118-130

Synthesized from the corresponding amino compound 2 in the same manneras in Example 66.

Example 118

1cm: yield 57%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.33 (m, 1H), 1.63 (m,7H), 2.00 (m, 2H), 2.21 (s, 3H), 2.44 (br s, 4H), 2.71 (br s, 4H), 3.10(s, 3H), 7.46 (t, J=9.2 Hz, 1H), 7.79 (m, 1H), 7.83(s, 1H), 8.12 (dd,J=2.7, 6.8 Hz, 1H), 8.39 (s, 1H), 8.60 (s, 1H), 10.06 (s, 1H).

Example 119

1cn: yield 62%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.44 (s, 6H), 2.30 (s,3H), 2.38 (s, 6H), 2.61(t, J=6.3 Hz, 2H), 2.83 (t, J=6.3 Hz, 2H), 2.99(s, 3H), 7.45 (t, J=9.2 Hz, 1H), 7.77 (s, 1H), 7.79(m, 1H), 8.11 (dd,J=2.7, 7.0 Hz, 1H), 8.27 (s, 1H), 8.54 (s, 1H), 9.97 (s, 1H).

Example 120

1co: yield 41%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.13 (t, J=7.0 Hz, 6H),2.17 (s, 3H), 2.39 (br s, 4H), 2.75 (br s, 4H), 3.08 (s, 3H), 3.52 (q,J=7.0 Hz, 4H), 3.67 (m, 4H), 7.45 (t, J=9.2 Hz, 1H), 7.78 (m, 1H), 7.82(s, 1H), 8.11 (dd, J=2.7, 7.0 Hz, 1H), 8.40 (s, 1H), 8.59 (s, 1H), 10.07(s, 1H).

Example 121

1cp: yield 56%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.45 (s, 6H), 2.34 (s,3H), 2.71(t, J=6.3 Hz, 2H), 3.12(s, 3H), 3.26 (s, 3H), 3.43 (t, J=6.3Hz, 2H), 7.47 (t, J=9.1 Hz, 1H), 7.81 (m, 1H), 7.84(s, 1H), 8.13 (dd,J=2.6, 6.9 Hz, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 10.08 (s, 1H).

Example 122

1cq: yield 63%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 2.78 (brs, 4H), 2.87 (s, 3H), 3.10 (s, 3H), 3.15 (br s, 4H), 7.46 (t, J=9.2 Hz,1H), 7.79 (m, 1H), 7.87(s, 1H), 8.12 (dd, J=2.4, 7.0 Hz, 1H), 8.45 (s,1H), 8.61 (s, 1H), 9.57 (br s, 1H),10.09 (s, 1H).

Example 123

1cr: yield 55%; ¹H NMR (270 MHz, DMSO-d6) δ ppm: 0.93 (t, J=7.3 Hz, 6H),1.74 (m, 4H), 2.19 (s, 3H), 2.41 (br s, 4H), 2.68(br s, 4H), 3.08 (s,3H), 7.45 (t, J=9.2 Hz, 1H), 7.77 (m, 1H), 7.81(s, 1H), 8.10 (dd, J=2.4,7.0 Hz, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 10.04 (s, 1H).

Example 124

1cs: yield 49%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.42 (m, 2H), 1.46 (s,6H), 1.89 (m, 2H), 2.37 (m, 2H), 2.97(m, 2H), 3.10 (S, 3H), 3.22(s, 3H),3.00-4.00 (m, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.79 (m, 1H), 7.83(s, 1H),8.11 (dd, J=2.7, 7.0 Hz, 1H), 8.44 (s, 1H), 8.61 (s, 1H), 10.08 (s, 1H).

Example 125

1ct: yield 34%; 1H NMR (270 MHz, DMSO-d₆) δ ppm: 1.47 (s, 6H), 1.99 (s,3H), 2.61 (br s, 2H), 2.68 (br s, 2H), 3.09(s, 3H), 3.44 (br s, 4H),7.45 (t, J=9.2 Hz, 1H), 7.78 (m, 1H), 7.84(s, 1H), 8.11 (dd, J=2.7, 7.0Hz, 1H), 8.44 (s, 1H), 8.60 (s, 1H), 10.08 (s, 1H).

Example 126

1cu: yield 69%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.06 (t, J=7.0 Hz, 3H),1.47 (s, 6H), 2.50 (m, 2H), 2.75 (q, J=7.0 Hz, 2H), 2.98 (t, J=7.0 Hz,2H), 3.11 (s, 3H), 3.59(s, 3H), 7.47 (t, J=9.2 Hz, 1H), 7.80 (m, 1H),7.83(s, 1H), 8.13 (dd, J=2.7, 7.0 Hz, 1H), 8.45 (s, 1H), 8.62 (s, 1H),9.52 (br s, 1H), 10.09 (s, 1H).

Example 127

1cv: yield 53%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.50 (brs, 6H), 2.69 (br s, 4H), 3.11 (s, 3H), 3.23 (s, 3H), 3.43(m, 2H), 7.47(t, J=9.2 Hz, 1H), 7.80 (m, 1H), 7.84(s, 20 1H), 8.13 (dd, J=2.4, 6.8Hz, 1H), 8.44 (s, 1H), 8.62 (s, 1H), 10.08 (s, 1H).

Example 128

1cw: yield 48%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.47 (s, 6H), 2.50-2.58(m, 6H), 2.65-2.70 (m, 6H), 3.12 (s, 3H), 7.47 (t, J=9.2 Hz, 1H), 7.81(m, 1H), 7.84(s, 1H), 8.14 (dd, J=2.7, 7.0 Hz, 1H), 8.47 (s, 1H), 8.62(s, 1H), 9,59 (br s, 1H),10.10 (s, 1H).

Example 129

1cx: yield 45%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 1.74 (brs, 4H), 2.76 (br s, 4H), 3.12(s, 3H), 7.47 (t, J=9.2 Hz, 1H), 7.79 (m,1H), 7.84(s, 1H), 8.13 (dd, J=2.4, 7.0 Hz, 1H), 8.45 (s, 1H), 8.62 (s,1H), 10.09 (s, 1H).

Example 130

1cy: yield 42%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 2.36 (s,3H), 2.68 (t, J=6.4 Hz, 2H),-2.82 (t, J=6.4 Hz, 2H), 3.12 (s, 3H), 7.47(t, J=9.0 Hz, 1H), 7.81 (m, 1H), 7.88(s, 1H), 8.13 (dd, J=2.4, 7.0 Hz,1H), 8.46 (s, 1H), 8.62 (s, 1H), 9.57 (s, 1H), 10.09 (s, 1H).

Example 131

UsingN⁴-(3-chloro-4-fluorophenyl)-6-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-4,7-quinazolinediamine(2a′) synthesized in Example 78 and in the same manner as in Example 1,the compound was converted to compound 1 a′. The crude product was leftstanding for three days and compound 1a′ (containing about 0.9equivalent amount of DMF) was obtained as needle crystals (yield 20%).

1a′: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.48 (s, 6H), 1.99 (s, 3H), 2.15(br s, 4H), 2.68 (br s, 4H), 5.88 (d, J=10.4 Hz, 1H), 6.36 (d, J=17.1Hz, 1H), 6.61 (dd, J=10.4, 17.1 Hz, 1H), 7.46 (t, J=9.1 Hz, 1H), 7.84(m, 1H), 8.20 (dd, J=2.5, 6.8 Hz, 1H), 8.32 (s, 1H), 8.61 (s, 1H), 8.67(s, 1H), 9.38 (s, 1H), 9.99 (s, 1H).

Example 132

Using 4ao (yield 60%) synthesized in the same manner as in SyntheticExample 7 using 4-oxotetrahydropyran and7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine as startingmaterials, and in the same manner as in Example 3, the compound wasconverted to 2ao and 1ao.

4ao: yield 60%; ¹H NMR (270 MHz, CDCl₃) δ ppm: 1.60-1.71 (m, 2H),1.87-1.93 (m, 2H), 2.29 (s, 3H), 2.40 (s, 1H), 2.49. (br s, 4H), 2.67(br s, 4H), 3.64-3.74 (m, 2H), 3.90-3.96 (m, 2H).

2ao: yield quantitative; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.53-1.65 (m,2H), 2.04-2.12 (m, 2H), 2.15 (s, 3H), 2.37(br s, 4H), 2.64 (br s, 4H),3.60 (m, 2H), 3.88 (m, 2H), 5.53 (s, 2H), 7.41 (t, J=9.2 Hz, 1H),7.53(s, 1H), 7.70 (s, 1H), 7.81 (m, 1H), 8.20 (dd, J=6.8, 2.7 Hz, 1H),8.39 (s, 1H), 9.64 (s, 1H).

1ao: yield 31%; ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.55 (m, 2H), 2.01 (m,2H), 2.15 (s, 3H), 2.36 (br s, 4H), 2.63 (br s, 4H), 3.61 (m, 2H), 3.84(m, 2H), 5.84 (d, J=10.0 Hz, 1H), 6.32 (d, J=17.0 Hz, 1H), 6.55 (dd,J=17.0, 10.0 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.85 (m, 1H), 7.90 (s,1H), 8.20 (br d, J=6.8 Hz, 1H), 8.64 (s, 1H), 8.65 (s, 1H), 9.96 (s,1H), 10.00 (s, 1H).

Example 133

A solution (4.5 mL) of acrylamide compound 1z (300 mg, 1.46 mmol)obtained by the method of Example 25 in dichloromethane was cooled to 0°C. to 5° C., and trifluoroacetic acid (TFA) (4.5 mL) was added. Themixture was stirred as it was for 1.5 hrs and the solvent was evaporatedunder reduced pressure. The residue was suspension-washed with diethylether and collected by filtration to give the objective compound

1ap.nTFA (50 mg).

1ap.nTFA : ¹H NMR (270 MHz, DMSO-d₆) δ ppm: 1.46 (s, 6H), 2.86 (br s,4H), 3.14 (br s, 4H), 5.87 (d, J=10.0 Hz, 1H), 6.34 (d, J=17.0 Hz, 1H),6.58 (dd, J=17.0, 10.0 Hz, 1H), 7.50 (t, J=9.2 Hz, 1H), 7.77 (m, 1H),7.92(s, 1H), 8.11 (m, 1H), 8.57 (br s, 2H), 8.75 (s, 1H), 8.77 (s, 1H),10.01 (s, 1H), 10.53 (br s, 1H).

Example 134

A solution (30 mL) of 4-(4-methyl-1-piperazinyl)-4-oxobutyric acid (0.69g, 10.0 mmol), N-methylpropargylamine (2.00 g, 10.0 mmol), EDC (2.88 g,15.0 mmol) and triethylamine (2.1 mL, 15.0 mmol) in DMF was stirred atroom temperature overnight. Water (40 mL) was added to the reactionmixture and the product was extracted with dichloromethane (40 mL×3).The extract was washed with aqueous sodium hydrogen carbonate andsaturated brine and concentrated under reduced pressure to give asolution (10.00 g) ofN-methyl-4-(4-methyl-1-piperazinyl)-4-oxo-N-(2-propynyl)butylamide (4aq)in DMF.

Using this DMF solution of 4aq and7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine and in thesame manner as in Example 3, the compound was converted to 1aq.

1aq:yield 7%; ¹H NMR (300 MHz, 354K, DMSO-d₆) δ ppm: 2.18 (s, 3H), 2.27(m, 4H), 2.60(m, 4H), 3.02 (s, 3H), 3.44 (m, 4H), 4.48 (s, 2H), 5.80(dd, J=10.1, 1.5 Hz, 1H), 6.33 (dd, J=16.8, 1.5 Hz, 1H), 6.60 (m, 1H),7.38 (t, J=9.2 Hz, 1H), 7.82 (m, 1H), 7.86 (s, 1H), 8.12 (m, 1H), 8.57(s, 1H), 8.78 (s, 1H), 9.55 (br s, 1H), 9.82 (br s, 1H); LC-MS: m/z=592(M⁺+1).

Example 135

Using 4ar (yield 97%) synthesized in the same manner as in SyntheticExample 7 using tert-butyl 4-oxo-1-piperidinecarboxylate instead of1,3-diethoxyacetone, and diethylamine instead of 1-methylpiperazine, and7-bromo-N-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine, 2ar (R═H)can be obtained according to a method similar to that of Example 3-1).This is reacted with a monoequivalent amount of di-tert-butyldicarboxylate (Boc₂O) under ice-cooling in dichloromethane for 30 minand a crude product was purified by silica gel column chromatography togive compound 2ar (R=Boc; total yield 85%). The compound 2ar (R=Boc) wasintroduced into 1ar′ by the method of Example 3-2) and converted to 1arby the method described in Example 142.

4ar: yield 97%; ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.06 (t, J=7.2 Hz, 6H),1.44 (s, 9H), 1.44-1.69 (m, 2H), 1.80-2.00 (m, 2H), 2.32 (s, 1H), 2.67(q, J=7.2 Hz, 4H), 2.96-3.19 (m, 2H), 3.77-4.09 (m, 2H).

2ar (R=Boc): yield 85%; ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.12 (t, J=7.1Hz, 6H), 1.47 (s, 9H), 1.65-1.81 (m, 2H), 1.91-2.11 (m, 2H), 2.78 (q,J=7.1 Hz, 4H), 3.07-3.27 (m, 2H), 3.83-4.09 (m, 2H), 4.47 (br s, 2H),6.98 (s, 1H), 7.15 (t, J=8.7 Hz, 1H), 7.24 (br s, 1H), 7.54 (m, 1H),7.86 (s, 1H), 7.93 (dd, J=2.5, 6.4 Hz, 1H), 8.58 (s, 1H).

1ar′: yield 63%; ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.04 (br t, 6H), 1.41(s, 9H), 1.52 (m, 2H), 2.02 (br d, J=12.3 Hz, 2H), 2.71 (br q, 4H), 3.12(m, 2H), 3.82 (br d, J=10.0 Hz, 2H), 5.82 (d, J=10.2 Hz, 1H), 6.31 (d,J=16.9 Hz, 1H), 6.51 (dd, 10.2, 16.9 Hz, 1H), 7.45 (t, J=9.1 Hz, 1H),7.84 (m, 1H), 8.19 (dd, J=2.6, 6.8 Hz, 1H), 8.61 (s, 1H), 8.64 (s, 1H),9.98 (br s, 2H).

1ar.nTFA: yield 76% (n=3); ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.29 (br s,6H), 2.03-2.24 (m, 2H), 3.05-3.65 (m, 10H), 5.90 (d, J=10.0 Hz, 1H),6.38 (d, J=17.0 Hz, 1H), 6.56 (dd, J=10.0, 17.0 Hz, 1H), 7.49 (t, J=9.1Hz, 1H), 7.80 (m, 1H), 8.16 (dd, J=2.3, 7.0 Hz, 1H), 8.19 (s, 1H),8.66-9.02 (m, 2H), 8.70 (s, 1H), 8.74 (s, 1H), 10.34 (s, 2H).

Example 136

Using the compound 4cz obtained by reacting propargylamine with ethylisonipecotinate in acetonitrile in the presence of potassium carbonatefrom ice-cooling to room temperature and7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine, and in thesame manner as in Example3,1-{3-[6-amino-4-(3-chloro-4-fluorophenylamino)-7-quinazolinyl]-2-propynyl}-4-piperidinecarboxylicacid ethyl ester (2cz) was obtained (yield 73%). The compound 2cz wasreacted in the same manner as in Example 66 and the crude product wassubjected to silica gel column chromatography. The obtained solid wastreated with an about 3 equivalent amount of 2N aqueous sodium hydroxidesolution in ethanol at room temperature for 2 hrs and neutralized togive precipitate. The product was collected by filtration andsuspension-washed with acetonitrile to give compound 1cz as apale-yellow solid (yield 57%).

4cz: yield 78%; ¹H NMR (300 MHz, CDCl₃) δ ppm: 1.25 (t, J=7.1 Hz, 3H),1.65-1.87 (m, 2H), 1.87-2.06 (m, 2H), 2.02-2.37 (m, 4H), 2.86 (m, 2H),3.30 (d, J=2.3 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H).

2cz: yield 73%.

1cz: ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.46-1.67 (m, 2H), 1.76-1.91 (m,2H), 2.16-2.39 (m, 3H), 2.80-2.94 (m, 2H), 3.08 (s, 3H), 3.75 (s, 2H),7.46 (t, J=9.1 Hz, 1H), 7.72-7.83 (m, 1H), 7.85 (s, 1H), 8.11 (br d,J=6.9 Hz, 1H), 8.35 (br s, 1H), 8.58 (s, 1H), 10.02 (br s, 1H).

Example 137

Using 3-methoxypropyne and7-bromo-N⁴-(3-chloro-4-fluorophenyl)-4,6-quinazolinediamine and in thesame manner as in Example 3, the compound was converted toN⁴-(3-chloro-4-fluorophenyl)-7-(3-methoxy-1-propynyl)quinazoline-4,6-diamine.According to the method described in Example 75,[2-(4-morpholino)ethanesulfonyl chloride was used instead ofmethanesulfonyl chloride]] to synthesize compound 1caa.

1caa: yield 10%; H NMR (300 MHz, CDCl₃) 5 ppm: 2.38-2.41 (m, 4H), 2.89(t, J=6.9 Hz, 2H), 3.38 (t, J=7.2 Hz, 2H), 3.50 (s, 3H), 3.61-3.68 (m,4H), 4.44 (s, 2H), 7.20 (t, J=9.0 Hz, 1H), 7.52-7.56 (m, 2H), 7.92-7.95(m, 2H), 8.05 (s, 1H), 8.07 (s, 1H), 8.73 (s, 1H).

Example 138

The compound 2t (Example 20) was converted to 1as according to themethod described in Example 1 [using 4-(4-morpholino)-2-butynoic acidinstead of acrylic acid].

1as: yield 17%; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 1.47 (br s, 8H), 1.72(br s, 6H), 2.11 (br s, 4H), 2.72 (br s, 6H), 7.45 (t, J=9.0 Hz, 1H),7.81-7.85 (m, 2H), 8.18 (d, J=5.1 Hz, 1H), 8.58 (s, 1H), 8.61 (s, 1H),9.62 (s, 1H), 9.96 (s, 1H).

Test Example 1 Evaluation of Tyrosine Kinase Inhibitor of the PresentInvention

(1) EGFR Tyrosine Kinase Inhibitory Action (method) Using EGF receptorpartially purified by A431 cell line (provided by Institute ofDevelopment, Aging and Cancer, Tohoku University, Cell Resource Centerfor Biomedical Research) derived from human epidermoid cancer, thetyrosine kinase assay of Linda J. Pike et al. (Proceedings of theNational Academy of Science of the U.S.A., 1982, 79, 1433) was improvedand performed. Specific method was as follows.

A431 cells were cultured in Dulbecco's Modified Eagle Medium (DMEM)containing 10% of fetal calf serum (FBS) at 37° C. under 5% carbondioxide gas, and homogenized in a solution containing 10 mMN-2-hydroxyethylpiperazino-N′-2-ethanesulfonic acid (Hepes) buffer (pH7.4), 0.25 M sucrose and 0.1 mM EDTA, and separated by centrifugation at3000 G for 5 min. The supernatant was separated by centrifugation at100,000 G for 30 min to separate A431 cell membrane fraction, which wasused for the assay as an enzyme source of partially purified EGFreceptor.

To a reaction mixture (final concentration 1% DMSO) containing theabove-mentioned A431 cell membrane fraction (10 to 15 ag), 30 mM Hepesbuffer (pH 7.7), 2 mM MnCl₂, 100 μM Na₃VO₄ and a test substancedissolved in dimethyl sulfoxide (DMSO) was added 100 ng of EGF, afterwhich 50 μg of synthetic substrate Angiotensin II(Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and a final concentration of 10 μM ofadenosine triphosphate (containing γ-³²P-labeled compound 37 KBq) wereadded to start the reaction. The volume then was 60 μL.

The reaction was carried out in ice for 30 min and 6 μL of 10 mg/mLbovine serum albumin and 25 μL of 20% trichloroacetic acid were added tostop the reaction. The reaction mixture was left in ice as it was for 30min.

The mixture was centrifuged at 5000 G for 2 min and the supernatant wassampled by 40 μL and adsorbed on P81 phosphocellulose paper. This wasimmersed in 0.75% aqueous phosphoric acid for 5 min for rinsing. Thisrinsing was repeated 4 times. The paper was taken out, the ³²P count wasmeasured on a liquid scintillation counter and this value was taken asA.

Simultaneously, a reaction without the test substance and a reactionwithout the test substance and EGF were also measured and the countsthereof were taken as B and C, respectively.

The tyrosine kinase inhibitory rate can be determined from the followingformula based on these values.Percent Inhibition (%)=100−{(A−C)/(B−C)}×100

The concentration of the test substance added was changed and thepercent inhibition was determined, and from which IC₅₀ value (50%inhibitory concentration) was calculated.

TABLE 11 Compound No. IC₅₀ nM 1a 1.8 1b 1.3 1c 3.9 1d 3.5 1e 2.4 1f 2.41g 4.4 1h 3.3 1i 3.7 1j 3.2 1k 1.9 1l 1.8 1m 1.9 1n 2.1 1o 4.6 1p <1 1q2.6 1r 1.5 1s 2.9 1t 2.6 1v <1 1x <1 1y <1 1aa 1.7 1ab 2.1 1ac <1 1ae <11ba 1.1 1bb 1.3 1bc 1.6 1bd 3.0 1be 8.0 1bf 0.82 1bg >10 1bh 4.4 1bi 1.01bj 2.9 1bk 2.1 1bl 2.2 1bm 2.8 1bn 3.5 1bo 2.2 1bp 2.1 1bq 3.8 1br 5.71bs 1.1 1bt 5.0 1bu 3.2 1bv 1.5 1bw 2.8 1bx 3.4 1by >10 1bz 2.2 1baa 2.81bab 5.6 1bac 1.2 1bad 4.0 1bae 2.5 1baf 3.3 1bag 5.1 1bah 2.6 1bai 1.81baj 3.3 1bak >10 1bal 3.2 1bam 3.3 1ban 2.6 1ca 7.7 1cb <1 1cd 2.1 1ce<1 1cg 2.1 1ch 2.6 1ci 1.9 1cj 2.7 1ck <1 1cl 6.7 1cm 5.2 1cn 2.9 1co10.3 1cp 3.1 1cq 2.1 1cr 3.4 1cs 5.3 1ct 2.1 1cu 5.5 1cv 1.8 1cw 2.5 1cx2.8 1ap 2.4(2) HER2 Tyrosine Kinase Inhibitory Action(Method)

As the cells, NIH3T3 mouse fibroblast cell line (provided by Instituteof Development, Aging and Cancer, Tohoku University Cell Resource Centerfor Biomedical Research) transformed with mutated c-erbB2 constitutivelyactivated by substituting valine at position 659 for glutamic acid wasused. In the following, the cell is referred to as A4 cell. This cellline was cultured in DMEM/F12 mixed medium (hereinafter a completemedium) supplemented with 10% FBS in a plastic dish at 37° C., 5% CO₂,95% air.

The A4 cells suspended in a complete medium were seeded in a 12-wellplate at 3×10⁵/well, and confluent cells were cultured with the compoundat 37° C. for 2 hrs. The cells were washed once with PBS, re-suspendedin a lysis buffer (60 mM Tris (pH 6.8), 2% SDS, 10% glycerol, 5%beta-mercaptoethanol, 0.001% bromophenol blue), treated byultrasonication and applied to Western blotting as a whole cell lysate.

The whole cell lysate (protein amount 25 μg) was applied to 7.5%SDS-polyacrylamide electrophoresis and transferred to PVDF membrane. Themembrane was blocked and incubated with antiphosphotyrosine mousemonoclonal antibody in Tris buffer containing 0.1% Tween 20 and thentreated with HRP-labeled antimouse second antibody. The membrane wasdeveloped with a chemiluminescent reagent. The chemiluminescence wastaken with a lumino CCD camera and recorded electronically. The obtainedphosphorylation signal was quantified with densitometer and evaluatedfor the inhibition of phosphorylation by the compound as expressed in %control, wherein the signal without addition of the compound was takenas 100% control and the background signal was taken as 0%.

TABLE 12 % of control % of control Compounds at 0.1 μM at 1 μM 1a 85 11f 61 31 1ap 74 24 1l 16 5 1ac 9 3(3) In vitro Cancer Cell Growth Inhibitory Action(Method)

A growth inhibitory test for various human cancer cell lines wasperformed by the XTT method. Specific method was as follows. The cellssuspended in RPMI1640 medium supplemented with 10% FBS were seeded in a96-well plate at 5,000/100 μ/1 well. Simultaneously, 100 μl/well of amedium containing a pharmaceutical agent diluted in 8 differentconcentrations of 100 μM to 0.04 μM at 3-fold ratio was seeded. For acompound that showed inhibitory activity at a low concentration, afurther lower dose was employed in the test. Thereafter, 1 mg/ml of XTTreagent (manufactured by SIGMA) supplemented with 25 μM of phenazinemethosulfate was added at 50 μl/well and the cells were incubated at 37°C. for about 4 hrs to allow staining of viable cells. Colorimetricdetermination (OD 490 nm) was done with a spectrophotometer.

IC₅₀ value (concentration inhibiting cell growth by 50%) was calculatedfrom a dose-inhibition curve and used as an index of inhibitoryactivity.

(4) In vivo Antitumor Effect

(Method)

Human epidermoid cancer cell A431 (5×10⁶/100 μl) suspended in PBS wassubcutaneously implanted on the back of Balb/c female nude mice(Balb/cAJcl-nu mouse, Clea Japan, Inc., 5-week-old when purchased) andwhen the average volume of the implanted tumor reached approximatelyabout 100 mm³ in about 7 days, the mice were allocated (4 per group) tomake the average tumor volume the same for each group. The tumor volumewas obtained by measuring the long diameter and the short diameter witha caliper and according to: [(short diameter)²×long diameter/2]=tumorvolume [mm³]. A pharmaceutical agent was forcibly administered orallyonce a day for 14 consecutive days from the day of the allocation, andthe drug was not given to the mice of the control group. The relativetumor growth rate, with the tumor volume of the day of start of theadministration as 1, was calculated for the control group and thetreatment group. Antitumor effect (%) of control=(relative tumor growthrate of treatment group on the last day −1)/(relative tumor growth rateof control group on the last day −1)×100

(Results)

The compound 1a, compound 1f and compound 1a.2TsOH showed adose-dependent antitumor effect. From these results, it has beenclarified that the compound of the present invention is useful as ananticancer agent.

TABLE 13 antitumor effect on A431 tumor pharmaceutical dose relativetumor % of agent [mg/kg] growth rate control control — 9.40 100 compound1a 0.3 6.47 65.1 compound 1a 1 4.93 46.8 compound 1a 3 2.70 20.3

TABLE 14 antitumor effect on A431 tumor pharmaceutical dose relativetumor % of agent [mg/kg] growth rate control control — 5.76 100 compound1f 1 5.63 97.2 compound 1f 10 1.09 1.8 compound 1a · 2TsOH 1 2.95 41.0(5) Mutagenicity Test(Evaluation Method)

To investigate the mutagenicity of compounds 1a and 1A (compound*described in Example 24 of JP-T-2000-508657), a reversion assay test(preincubation method) was performed using Salmonella typhimurium TA100,TA98, TA2637 and Escherichia coli WP2uvrA. Each compound in the dose offrom 50 (78.1 for compound 1A) to 5000 μg/plate was pretreated at 37° C.for 20 min in the co-existence or absence of S9mix derived from ratliver and layered on the minimum glucose agar medium along with softagar. After incubation at 37° C. for about 48 hrs, the revertantcolonies emerged on the plate were counted. When the number of therevertant colonies in the treated plate increased in a dose-dependentmanner and reached not less than 2 times the solvent control value, theresult was evaluated to be positive.

(Results)

The compound 1a did not induce an increase in the revertant colony, suchas that exceeding 2 times the solvent control value, in any strain. Incontrast, compound 1A induced a distinct increase in the revertantcolony both in TA98 and TA2637, which exceeds 2 times the solventcontrol value, irrespective of metabolism activation.

From the above results, it has been concluded that compound 1a ismutagenicity negative, and compound 1A is mutagenicity positive.

*

INDUSTRIAL APPLICABILITY

Since the compound (I) of the present invention has a potent tyrosinekinase inhibitory activity (cancer cell growth inhibitory action), itcan be used as an anticancer agent as well as an agent for the treatmentand/or prophylaxis of psoriasis and the diseases based onarteriosclerosis.

This application is based on patent application Nos. 45827/2001 and353525/2001 filed in Japan, the contents of which are all herebyincorporated by reference.

1. A quinazoline derivative of the following formula (1a)

or a pharmaceutically acceptable salt thereof, a hydrate thereof, anoptically active compound thereof, a racemate thereof or a diastereomermixture thereof.
 2. The quinazoline derivative of claim 1, wherein thepharmaceutically acceptable salt is a salt with tosic acid.
 3. A crystalof a salt with tosic acid of a compound of the following formula (1a)


4. The crystal of claim 3 having any one, two, three, four, five, six orall the characteristic absorbance peaks (2θ) shown below in powder X-raydiffraction pattern: characteristic peaks (2θ, ±0.2°) 33°, 6.6°, 7.5°,94°, 13.9°, 17.4°, 19.1°.
 5. The quinazoline derivative of claim 1,wherein the hydrate is a ½ hydrate.
 6. A crystal of a ½ hydrate of acrystal of a compound of the following formula (1a)


7. The crystal of claim 6 having any one, two, three, four, five, six orall the characteristic absorbance peaks (2θ) shown below in powder X-raydiffraction pattern: characteristic peaks (2θ, ±0.2°) 7.1°, 10.6°,11.9°, 12.2°, 13.8°, 17.3°, 18.4°.
 8. A pharmaceutical compositioncomprising a quinazoline derivative of claim 1 and a pharmaceuticallyacceptable carrier.
 9. A method for the treatment of a solid tumor,which comprises administering to a patient in need thereof atherapeutically effective amount of a quinazoline derivative of claim 1as an active ingredient.